@article {pmid42033998,
year = {2026},
author = {Yang, B and Earnest, T and Bilgel, M and Albert, MS and Johnson, SC and Davatzikos, C and Erus, G and Masters, CL and Resnick, SM and Miller, MI and Bakker, A and Morris, JC and Benzinger, TLS and Gordon, BA and Sotiras, A and , and , },
title = {Predicting future cognitive impairment in preclinical Alzheimer's disease using amyloid PET and MRI: A multisite machine learning study.},
journal = {Neurobiology of aging},
volume = {165},
number = {},
pages = {8-23},
doi = {10.1016/j.neurobiolaging.2026.04.005},
pmid = {42033998},
issn = {1558-1497},
abstract = {Predicting the likelihood of developing Alzheimer's disease (AD) dementia in at-risk individuals is important for the design of and optimal recruitment for clinical trials of disease-modifying therapies. Machine learning (ML) has been shown to excel in this task; however, there remains a lack of models developed specifically for the preclinical AD population, who display early signs of abnormal brain amyloidosis but remain cognitively unimpaired. Here, we trained and evaluated ML classifiers to predict whether individuals with preclinical AD will progress to mild cognitive impairment or dementia within multiple fixed time windows, ranging from one to five years. Models were trained on regional imaging features extracted from amyloid positron emission tomography and magnetic resonance imaging pooled across seven independent sites and from two amyloid radiotracers ([[18]F]-florbetapir and [[11]C]-Pittsburgh-compound-B). Out-of-sample generalizability was evaluated via a leave-one-site-out and leave-one-tracer-out cross-validation. Classifiers achieved an out-of-sample receiver operating characteristic area-under-the-curve of 0.66 or greater when applied to all except one hold-out sites and 0.72 or greater when applied to each hold-out radiotracer. Additionally, when applying our models in a retroactive cohort enrichment analysis on A4 clinical trial data, we observed increased statistical power of detecting differences in amyloid accumulation between placebo and treatment arms after enrichment by ML stratifications. As emerging investigations of new disease-modifying therapies for AD increasingly focus on asymptomatic, preclinical populations, our findings underscore the potential applicability of ML-based patient stratification for recruiting more homogeneous cohorts and improving statistical power for detecting treatment effects for future clinical trials.},
}

@article {pmid42034805,
year = {2026},
author = {Monteiro, R and Dunn, JT and Rodriguez, G and Fisher, DW and Dong, H},
title = {Targeting central immune signaling enhances the effects of methylphenidate in alleviating apathy-like behavior in 5xFAD mice.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-49172-0},
pmid = {42034805},
issn = {2045-2322},
support = {R01AG062249-05, 5R01AG079989-03//National Institute of Aging/ ; },
abstract = {Beyond cognitive impairment, Alzheimer's disease (AD) is frequently accompanied by apathy, the most prevalent and burdensome neuropsychiatric symptom (NPS). Apathy significantly impacts AD onset and progression, yet its molecular underpinnings remain unclear. Our previous RNA-sequencing analysis revealed abnormal immune gene expression uniquely associated with apathy in AD patients. In this study, we investigated whether changes in these immune related genes are also linked to apathy-like behavior, and whether administration of C3a receptor antagonist SB290157, alone or with methylphenidate, modifies apathy-like behaviors in 5xFAD mice. We first validated the apathy-related immune hub genes identified in human AD in the prefrontal cortex (PFC) of 16-18 month-old 5xFAD mice using RT-qPCR. Then separate cohorts of similarly aged 5xFAD mice received SB290157 and/or methylphenidate for three weeks. Our results showed that elevated immune hub genes Tyrobp, C3, C3ar, C1qa, C1qb, and C1qc were strongly correlated with apathy-like behavior in 5xFAD mice. Combined SB290157 and methylphenidate treatment improved nest-building behavior, reduced C3 and C3ar expression as well as restored dendritic spine density in the PFC. Our results confirm complement-mediated immune dysregulation is linked to apathy and suggest that co-targeting complement and catecholaminergic pathways may offer a novel therapeutic strategy for alleviating apathy in AD.},
}

@article {pmid42036797,
year = {2026},
author = {Bonta, KM and Li, JS and Tun, SM and Fredericks, CA},
title = {Sleep duration and amyloid status moderate the association between mood symptoms and amygdalar tau in preclinical Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71447},
doi = {10.1002/alz.71447},
pmid = {42036797},
issn = {1552-5279},
support = {K23AG059919/NH/NIH HHS/United States ; 2019-AACSF-644153/ALZ/Alzheimer's Association/United States ; //The McCance Foundation/ ; },
mesh = {Humans ; *Alzheimer Disease/metabolism/diagnostic imaging/psychology ; Male ; Female ; *tau Proteins/metabolism ; Positron-Emission Tomography ; Aged ; *Amygdala/metabolism/diagnostic imaging ; *Anxiety/metabolism ; *Sleep/physiology ; *Depression/metabolism ; Longitudinal Studies ; *Amyloid beta-Peptides/metabolism ; Aged, 80 and over ; Prodromal Symptoms ; Sleep Duration ; },
abstract = {INTRODUCTION: Anxiety and depressive symptoms are common in Alzheimer's disease (AD), yet their relationships with amyloid, tau, and sleep remain unclear. We examined whether amyloid status and sleep duration moderate the relationships between anxiety and depressive symptoms and amygdalar tau burden in cognitively unimpaired older adults at risk for AD.

METHODS: Participants (n = 393) from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) and the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) studies underwent tau and amyloid positron emission tomography imaging. Anxiety and depressive symptoms were evaluated using the State-Trait Anxiety Inventory and Geriatric Depression Scale. Sleep duration was self-reported.

RESULTS: Positive amyloid status moderated the relationship between depressive symptoms and amygdalar tau. Sleep duration moderated the relationship between anxiety and amygdalar tau, such that greater anxiety symptoms were associated with higher tau levels at shorter sleep durations.

DISCUSSION: Findings suggest biological and behavioral factors jointly influence neuropsychiatric symptom-tau relationships in preclinical AD, supporting an interactive model of early disease vulnerability.},
}

Humans
*Alzheimer Disease/metabolism/diagnostic imaging/psychology
Male
Female
*tau Proteins/metabolism
Positron-Emission Tomography
Aged
*Amygdala/metabolism/diagnostic imaging
*Anxiety/metabolism
*Sleep/physiology
*Depression/metabolism
Longitudinal Studies
*Amyloid beta-Peptides/metabolism
Aged, 80 and over
Prodromal Symptoms
Sleep Duration

@article {pmid42037680,
year = {2026},
author = {Sirajo, MU and Obie, R and Mukhtar, AI and Abdullahi, NM and Taniyohwo, EM and Oyem, JC and Badamasi, IM},
title = {Targeting VDR-RXR heterodimerization in neurodegenerative diseases: a hypothetical framework for combined vitamin D3 and vitamin A therapy.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1754364},
pmid = {42037680},
issn = {1664-2295},
abstract = {Neurodegenerative diseases such as Alzheimer's and Parkinson's disease are characterized by progressive neuronal loss, oxidative stress, and limited treatment options. While vitamin D3 has demonstrated neuroprotective potential, we hypothesize that its co-administration with vitamin A may enhance therapeutic effects via synergistic interactions between their nuclear receptors (the vitamin D Receptor (VDR) and Retinoid X Receptor (RXR)). The interaction leads to the formation of a heterodimer, which regulates genes involved in neuronal survival, inflammation, and oxidative balance. A comprehensive literature review was conducted to evaluate the mechanisms underlying Vitamin D3's neuroprotection and Vitamin A's modulatory role through RXR activation, focusing on studies exploring the VDR-RXR heterodimer in Alzheimer's and Parkinson's disease models. Evidence indicates that vitamin D3 mitigates neurodegeneration by upregulating neuroprotective genes, reducing oxidative stress, and modulating calcium homeostasis, with these effects amplified by RXR activation. The VDR-RXR heterodimer interaction appears critical for enhancing transcriptional activity, promoting neuronal resilience, while potentially slowing neurodegeneration progression. We propose that combined vitamin D3 and vitamin A supplementation could offer a promising therapeutic strategy by synergistically optimizing VDR-RXR signaling, thereby improving neuroprotection. This hypothesis requires validation through an integrated approach that includes molecular, cellular, behavioral, and translational neuroimaging methods to investigate neuroprotective effects associated with VDR-RXR co-activation.},
}

@article {pmid42038088,
year = {2026},
author = {Permoda-Pachuta, A and Obszanski, P and Grad, Z and Futyma-Jędrzejewska, M and Ziemecki, P and Dominiak, M},
title = {Depression as an early symptom and risk factor of dementia - a narrative review.},
journal = {Frontiers in psychiatry},
volume = {17},
number = {},
pages = {1786179},
pmid = {42038088},
issn = {1664-0640},
abstract = {Depression is a common psychiatric disorder, while dementia represents a growing global health challenge, particularly in aging populations. Although substantial progress has been made in pharmacotherapy, neurodegenerative processes can only be partially slowed, and disease progression cannot be completely halted. Neurodegenerative diseases therefore remain largely incurable, underscoring the importance of early recognition and intervention. This raises an important clinical and conceptual question: does depression represent an early manifestation of dementia, act as a risk factor for its development or both? Understanding these relationships is essential for accurate diagnosis, appropriate treatment, and timely implementation of preventive strategies. This article presents a narrative review of the literature examining the complex relationship between depression and dementia, with a focus on clinical presentation, diagnostic challenges, and neurobiological mechanisms. Neuroimaging techniques such as MRI and PET, and in selected contexts SPECT, support the differential diagnosis of depression and dementia, although limitations in sensitivity and specificity persist. Inflammation has been extensively investigated as a shared pathological mechanism underlying both conditions. Emerging evidence also suggests that anti-amyloid therapies may be associated with improvements in depressive symptoms in selected patient populations, further highlighting overlapping pathophysiological pathways between depression and dementia. Improved understanding of the interplay between depression and dementia may facilitate earlier diagnosis, reduce diagnostic uncertainty, and support the development of more effective preventive and therapeutic strategies.},
}

@article {pmid42038337,
year = {2026},
author = {Hong, R and Han, J and Dong, F and Kalsoom, UE and Cao, C and Zhou, A and Wu, Q and Qu, X},
title = {Cynanchum bungei Decne-derived extracellular vesicles alleviate cognitive impairment and pathological damage in Alzheimer's disease.},
journal = {Frontiers in cellular neuroscience},
volume = {20},
number = {},
pages = {1798965},
pmid = {42038337},
issn = {1662-5102},
abstract = {INTRODUCTION: Cynanchum bungei Decne (CB) is known for its therapeutic benefits for neurodegenerative conditions as anti-inflammatory, antioxidant, and barrier significantly limits their potential advantages. Given the ability of crossing the barrier with minimal toxicity, extracellular vesicles derived from CB (CB-EVs) were utilized as an innovative approach to mitigate Alzheimer's disease (AD).

METHODS: CB-EVs were isolated using gradient ultracentrifugation and identified via TEM imaging, nanoparticle tracking analysis, marker identification, and in vivo imaging system. Ten-month-old triple transgenic AD (3xTg-AD) mice received intravenous administration of CB-EVs at doses of 10 or 20 mg/kg every 3 days for the cognitive and pathological assessments. The human APP Swedish mutation transgenic SH-SY5Y cells were constructed as Aβ-induced neural damage model, and different concentrations of CB-EVs were added into medium to analyze its roles on cell viability, transcriptome changes, oxidative stress, and mitochondrial damage.

RESULTS: CB-EVs exhibited standard morphological and molecular traits, accumulating in the cerebral cortex and hippocampus. Two months of CB-EVs treatment alleviated cognitive impairments, diminished Aβ plaque, reduced Tau protein hyperphosphorylation, and lessened neuronal loss in 3xTg-AD mice. In transgenic SH-SY5Y cells, CB-EVs improved cell viability, enhanced superoxide dismutase activity, downregulated oxidative stress related NUPR1 and CHOP expression, decreased reactive oxygen species, lipid peroxidation, and malondialdehyde levels, reduced mitochondrial damage.

CONCLUSION: These results demonstrated that CB-EVs could protect neurons from oxidative stress, attenuate cognitive impairment and pathological damage in AD.},
}

@article {pmid42038539,
year = {2026},
author = {K, V and Jaisankar, N},
title = {Design of a deep learning prediction model for Alzheimer's and Parkinson's Disease using MRI images.},
journal = {Frontiers in artificial intelligence},
volume = {9},
number = {},
pages = {1777236},
pmid = {42038539},
issn = {2624-8212},
abstract = {INTRODUCTION: Alzheimer's disease (AD) and Parkinson's disease (PD) are types of neurodegenerative diseases that affect the body and get worse over time. The cause of AD mainly involves the buildup of protein which are abnormal, issues with the immune reaction, death of neurons. Different from this, the death of the neurons that make dopamine leads to PD and causes both motor and non-motor problems. MRI images are used to provide an early and correct diagnosis to enable timely treatment planning and management of the disease.

METHODS: In this paper, a design of an AI-based deep learning framework is proposed for the classification of neurodegenerative disease based on the brain MRI data. The pipeline that we propose begins with data preparation including data augmentation using InceptionGAN for augmentation of the dataset and fixing of class imbalance issues. A composite method of feature extraction using ConvNeXt and MaxViT along with the Cross-Fusion Attention model, worked well to capture local and global spatial features. Bayesian Optimization and Genetic Algorithm are used to optimize hyperparameters for improving the performance of the model.

RESULTS: The Hybrid Deep Neural Network (HDNN) is the last classifier with an accuracy of 97.4%. Based on performance accuracy, F1-score, the model is strong and reliable. We used Gradient-weighted Class Activation Mapping++ to explain how regions of interest in the brain influence our model's decisions.

DISCUSSION: This study offers an interpretable and high-performing deep learning framework for the early and precise prediction of neurodegenerative disorders utilizing MRI imaging, thereby enhancing clinical decision-making and patient care.},
}

@article {pmid42038695,
year = {2026},
author = {Wang, X and Tian, L},
title = {The therapeutic efficacy of transcranial direct current stimulation in managing Alzheimer's disease: a systematic review and meta-analysis.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1726469},
pmid = {42038695},
issn = {1663-4365},
abstract = {OBJECTIVE: The present study aimed to investigate the therapeutic efficacy of transcranial direct current stimulation (tDCS) for Alzheimer's disease (AD) and identify potential influential factors.

METHODS: A comprehensive literature search was conducted in PubMed, Embase, Web of Science, and the Cochrane Library up to April 2025. Eligible studies were randomized controlled trials (RCTs) in which tDCS was the sole differential intervention between study arms. The pooled effects of tDCS on patients' global cognition, language, memory, executive function, and emotion were evaluated. Subgroup analyses were also performed to identify potential influential factors.

RESULTS: A total of 23 studies involving 24 trials and 823 mild to moderate AD patients were included. Our meta-analysis showed that tDCS significantly improved global cognition in AD patients (standardized mean difference [SMD] = 0.66; 95% confidence interval [CI], 0.38-0.95; p < 0.01), but had no significant effects on language or emotion. Subgroup analyses further revealed that significant memory improvement was observed in patients who received ≤ 10 sessions of tDCS and those with >6 years of education. Additionally, executive function was improved in patients who received stimulation on the left dorsolateral prefrontal cortex and in tDCS groups with ≤ 10 sessions. Moreover, improved executive function was observed in patients with 6-10 years of education, but not in other subgroups.

CONCLUSION: tDCS treatment leads to improvements in global cognition, memory, and executive function in AD patients, but not in language or psychomotor symptoms. However, due to the relatively high heterogeneity of the included data, further well-designed studies are warranted before tDCS can be established as a standard therapeutic approach for AD.},
}

@article {pmid42038702,
year = {2026},
author = {Zhao, S and Shi, H and Guan, C and Zeng, Q and Zhang, C and Wan, Y},
title = {Research on Alzheimer's disease MRI image classification based on spatial attention mechanism.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1657578},
pmid = {42038702},
issn = {1663-4365},
abstract = {INTRODUCTION: Early diagnosis of Alzheimer's Disease (AD) is crucial for improving patient quality of life and treatment outcomes. However, accurately classifying MRI scans of AD remains challenging due to the subtle and spatially complex nature of lesion regions. This study proposes a novel bidirectional spatial attention mechanism to enhance the focus on key pathological features in AD MRI images, aiming to improve classification accuracy and support earlier intervention.

METHODS: To enhance model performance, we introduced a customized bidirectional spatial attention module (ATT) integrated into a Swin-Tiny Transformer backbone. Unlike conventional attention methods, the ATT module generates spatial attention maps by adaptively pooling features along both vertical and horizontal orientations, allowing refined adjustment of attention weights across different image regions. Furthermore, to address issues of limited sample size and class imbalance, we employed data augmentation and expansion strategies, enriching the diversity of training data. The model was trained and evaluated on the augmented OASIS1 dataset.

RESULTS: The improved Swin-Tiny+ATT model demonstrated significant performance gains across all key metrics on the augmented dataset. Compared to the baseline Swin Transformer, accuracy improved from 84.83% to 87.96%, recall from 89.82% to 91.92%, precision from 85.27% to 91.98%, and the F1 score from 87.26% to 91.89%. These results confirm that the ATT module effectively enhances the model's ability to capture complex spatial features and identify critical lesion regions.

DISCUSSION: The proposed Swin-Tiny+ATT model exhibits strong potential for improving MRI-based classification of Alzheimer's Disease. The bidirectional spatial attention mechanism successfully directs the model's focus to relevant anatomical regions, contributing to higher precision and recall. Combined with data augmentation strategies, the approach mitigates class imbalance and enhances generalization. This work provides a promising deep learning framework to support early and accurate diagnosis of AD, with implications for clinical decision-making and personalized treatment planning.},
}

@article {pmid42039150,
year = {2026},
author = {Ouro, A and Ben-Dor, GA and Debasa-Mouce, M and Gulkarov, S and De Leon, J and Castro-Mosquera, M and Sobrino, T and Bougea, A and Reiss, AB},
title = {Monoclonal antibodies and small molecules: on the cutting edge of Alzheimer's disease therapy.},
journal = {Frontiers in cell and developmental biology},
volume = {14},
number = {},
pages = {1766762},
pmid = {42039150},
issn = {2296-634X},
abstract = {Alzheimer's disease (AD) remains a major global health challenge, with prevalence projected to increase dramatically in the coming decades and no effective treatments available. Current therapies offer only symptomatic relief, reinforcing the need for disease-modifying strategies targeting underlying pathogenic mechanisms. Advances in understanding amyloid-β (Aβ) and tau pathology have propelled the development of targeted interventions, particularly monoclonal antibodies (mAbs) and small-molecule therapeutics. Recent anti-Aβ antibodies, such as aducanumab, lecanemab, and donanemab, have demonstrated significant biological activity and reductions in amyloid burden, leading to regulatory approvals that represent important proof-of-concept milestones. However, these therapies face ongoing controversies related to modest clinical efficacy, accessibility, cost, and safety concerns. In parallel, small-molecule development has expanded beyond failed secretase inhibitors toward more refined mechanisms, including tau aggregation inhibition, kinase modulation, mitochondrial stabilization, and anti-inflammatory pathways. These compounds offer advantages in oral administration, blood-brain barrier penetration, and multi-target engagement. Together, mAbs and small molecules represent complementary therapeutic strategies addressing different aspects of AD pathophysiology. Their integration with emerging biomarkers, genetic profiling, and early diagnostic frameworks is driving a transition toward personalized and stage-specific treatment approaches. This review synthesizes current mechanistic insights, clinical evidence, and translational challenges of both modalities, highlighting how their convergence may shape the next-generation of AD therapeutics.},
}

@article {pmid42039285,
year = {2026},
author = {Chen, Y and Sun, X and Xi, Y and Luo, Z and Lai, H and Zhu, D and Zhang, Y and Xu, F and Li, J and Zhou, J and Ding, Y and Zhang, H},
title = {Pathology-directed drug delivery strategies: How to overcome blood-brain barrier for the treatment of brain diseases.},
journal = {Acta pharmaceutica Sinica. B},
volume = {16},
number = {4},
pages = {2250-2281},
pmid = {42039285},
issn = {2211-3835},
abstract = {Despite the different degrees of blood-brain barrier (BBB) damage in diverse brain diseases, it remains a formidable barrier that restricts most drugs from penetrating the brain. A comprehensive understanding and elucidation of the disease-specific changes of BBB in various brain pathologies are essential for directing the customized brain-targeted drug delivery systems, potentially improving cerebral delivery efficiency and therapeutic efficacy. Hence, this review compared anatomical and physiological changes of BBB under healthy and pathological states and discussed the effects of these changes on cerebral delivery efficiency. Thereafter, a particular emphasis was placed on the pathology-directed drug delivery strategies tailored to different brain diseases, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, stroke, and brain tumors. By combining insights from cutting-edge studies and emerging technologies, we proposed forward-looking suggestions on future directions to brain-targeted drug delivery, thereby improving the therapeutic efficacy and accelerating the translation from preclinical attempts into clinical practice.},
}

@article {pmid42039533,
year = {2026},
author = {Lucciola, R and Herdy, JR and Vajaphattana, Y and Karbacher, L and Sabedot, TS and Cuoco, MS and Traxler, L and Kang, A and Reynolds, M and Jones, JR and Schafer, ST and Mertens, J and Gage, FH},
title = {RUNX1 and YY1 modulate neuronal fate and energy metabolism in Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.13.716801},
pmid = {42039533},
issn = {2692-8205},
abstract = {Loss of neuronal identity and metabolic dysfunction are features of Alzheimer's disease (AD), yet the upstream-acting molecular drivers remain incompletely understood. By integrating multi-omics data from patient-derived induced neurons (iNs) and AD post-mortem human brains, we discovered that AD neurons express two master transcription factors (TFs), RUNX1 and YY1. While these TFs are primarily expressed during development where they play fundamental roles in cell fate determination and cellular bioenergetics, respectively, they can be reactivated in adult neurons in response to stress. To understand their functional role in AD neurons, we overexpressed RUNX1 or YY1 in aged iNs and found that the expression of each TF was sufficient to recapitulate two AD-associated features. Specifically, RUNX1 overexpression caused loss of neuronal fate, whereas YY1 overexpression regulated gene regulatory programs associated with metabolic dysfunction. Conversely, downregulation of either TF, in AD iNs, reinstated gene regulatory programs associated with a healthy mature neuronal phenotype. Together, these findings identify two transcriptional master regulators of the AD neuronal phenotype and establish a mechanistic foundation for further studying their role in the pathogenesis of AD and as putative therapeutical targets for the treatment of AD and age-associated neurodegeneration.},
}

@article {pmid42039828,
year = {2026},
author = {Li, Z and Xie, C and Pan, C},
title = {The oral-gut-brain axis: how periodontitis influence depression.},
journal = {Frontiers in microbiology},
volume = {17},
number = {},
pages = {1778744},
pmid = {42039828},
issn = {1664-302X},
abstract = {Depression has a high global prevalence and is a common mental-emotional disorder that severely jeopardizes human health. However, current treatment options remain limited, necessitating the exploration of novel pathological mechanisms and intervention targets. Recent studies indicate that periodontitis, as a prevalent chronic oral infectious disease, not only causes local microbial dysbiosis and inflammatory responses but may also influence central nervous system function through the "oral-gut-brain axis," thereby contributing to the pathogenesis and progression of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis, as well as neuropsychiatric disorders like depression. This review systematically examines the impact of periodontitis on oral microbiota and its subsequent translocation and colonization in the gut microbiota through pathways including swallowing and bloodstream circulation, ultimately leading to structural and functional dysregulation of the gut microbiota. The interaction between oral and gut microbiota can influence the brain through the "gut-brain axis," including disturbances in neurotransmitter metabolism, activation of systemic immune responses, and direct or indirect effects of bacterial metabolites (such as short-chain fatty acids, lipopolysaccharides, etc.) on the blood-brain barrier and neural function. This suggests that periodontal health management may serve as a novel strategy for the prevention and treatment of depression. This article further summarizes the potential of oral interventions for periodontitis (such as mechanical debridement and local/systemic antimicrobial therapy), microbiota modulation methods (such as probiotics, prebiotics, and fecal microbiota transplantation), and multidisciplinary collaborative comprehensive treatment strategies in improving microbial homeostasis and alleviating depressive symptoms. Finally, this paper points out the current research limitations in mechanistic details, causal relationships, and clinical translation, while envisioning the feasibility and prospects of developing personalized treatment strategies by targeting the "oral-gut-brain axis" in the future.},
}

@article {pmid42039925,
year = {2026},
author = {Lennon, MJ and Xu, Y and Thalamuthu, A and Mather, K and Sachdev, PS},
title = {Druggable genome-wide Mendelian randomization analysis identifies potential treatment targets in vascular dementia.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {},
pages = {e70258},
pmid = {42039925},
issn = {2352-8737},
abstract = {BACKGROUND: There are currently no US Food and Drug Administration-approved treatments for vascular dementia (VaD). Genome-wide approaches have successfully identified druggable targets and treatments for various disorders. In this study, we performed druggable genome-wide two-sample Mendelian randomization (2SMR) analysis to identify possible treatment targets for VaD.

METHODS: 2SMR analyses were used to estimate the causal effects of druggable gene expression on VaD risk. The exposure variables were significant cis-expression quantitative trait loci (eQTLs) and cis-protein quantitative trait loci (pQTLs) in the cerebrospinal fluid (CSF), brain, and plasma. The main outcome variable was genetic VaD risk, based on the Mega Vascular Cognitive Impairment and Dementia Consortium genome-wide association study. 2SMR analysis examined the causal relationship between eQTLs/pQTLs and imaging markers of VaD. A phenome-wide 2SMR analysis explored the relationships between significant druggable genes and phenotype summary statistics derived from the UK Biobank. False discovery rate (FDR) P value corrections were applied to all analyses.

RESULTS: A total of 12,224 druggable genes were identified from the Drug-Gene Interaction Database (DGIdb) and associated papers. Of these, the 2SMR analysis identified four FDR-significant genes in the pQTL analysis, with none identified among the eQTLs. In the CSF, TOMM40 had a significant (P = 3.67E-36) effect on VaD outcomes as well as cerebral small vessel disease (cSVD), white matter hyperintensities (WMH; P = 0.0001) and fractional anisotropy (FA; P = 0.0028). In the brain, apolipoprotein E (APOE; P = 1.90E-54) was associated with VaD and three cSVD markers: WMH (P = 1.61E-06), FA (P = 0.0018), and mean diffusivity (P = 0.0244). ERAP1 (P = 0.0163), and SAA1-4 (P = 0.0163) showed weaker associations with VaD, did not show colocalization, and were not associated with cSVD imaging markers.

DISCUSSION: This study identified four potential drug targets for VaD, using a 2SMR analysis approach. Two genes, APOE and TOMM40, are well understood to be associated with both Alzheimer's disease and VaD, whereas the other two, ERAP1 and SAA1-4, are novel targets involved in immune system regulation and inflammation.},
}

@article {pmid42040886,
year = {2026},
author = {Fawad, A and van der Landen, SM and Tideman, P and van der Putten-Toorenburg, A and Butterbrod, E and Smith, R and van Westen, D and Calling, S and Midlöv, P and Mattsson-Carlgren, N and Borgström Bolmsjö, B and Stomrud, E and Nilsson, MH and Hansson, O and Sikkes, SAM and Palmqvist, S},
title = {Clinical staging in Swedish primary care using the Amsterdam Instrumental Activities of Daily Living Questionnaire.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {},
pages = {e70344},
pmid = {42040886},
issn = {2352-8729},
abstract = {INTRODUCTION: We assessed the accuracy of the Amsterdam Instrumental Activities of Daily Living Questionnaire (A-IADL-Q) for clinical staging in Swedish primary care.

METHODS: Participants from the Swedish BioFINDER Primary Care study were included. Discriminative performance of the A-IADL-Q was evaluated using receiver operating curves. Multinomial and linear regression models assessed associations among A-IADL-Q scores, clinical stage, demographics, cognition, and comorbidities.

RESULTS: Among 623 patients, 148 (23.8%) had subjective cognitive decline (SCD), 274 (43.9%) mild cognitive impairment (MCI), and 201 (32.3%) dementia with a mean (standard deviation) age of 76.7 (7.3). The area under the curve (95% confidence interval) for discriminating between SCD versus MCI/dementia was 0.89 (0.86-0.91) and for SCD/MCI versus dementia 0.89 (0.87-0.92). Age (β = -0.25), Mini-Mental State Examination (β = 0.91) and Montreal Cognitive Assessment (β = 0.57), but no other demographics and comorbidities, were associated with the A-IADL-Q.

DISCUSSION: The A-IADL-Q may help primary care physicians determine clinical stage and shows promise for use to adequately refer patients to secondary or tertiary care.},
}

@article {pmid42041219,
year = {2024},
author = {Xie, P and Sun, C and Li, Y and Deng, Y and Xie, C},
title = {Clinical Study on Mesenchymal Stem Cell Factors Therapy for Alzheimer's Disease.},
journal = {Nigerian journal of clinical practice},
volume = {27},
number = {10},
pages = {1216-1220},
doi = {10.4103/njcp.njcp_561_24},
pmid = {42041219},
issn = {1119-3077},
abstract = {BACKGROUND: Alzheimer's disease (AD), characterized by cognitive decline, lacked effective cures. Mesenchymal stem cell (MSC) factors (MSCFs) offered a new approach by promoting brain tissue repair and modulating immune responses, presenting a promising alternative to AD treatment with minimal risks.

AIM: This study aimed to investigate the effects of MSCF on AD and to compare the effects with traditional MSC treatments.

METHODS: Sixty patients were divided into control and observation groups, with 30 cases in each group. The control group were injected intravenously with 10 mL of MSCs (5.0 × 10 9 L -1) plus 100 mL normal saline (once every 5 days for six consecutive treatments). The observation group received intramuscular injections of 0.5 mL (1 mL for the first dose) of MSCF (every other day for 15 consecutive treatments). Amyloid-β 42 (Aβ42) and Tau protein concentrations in cerebrospinal fluid were determined by ELISA pretreatment and at 1, 3, and 6 months' post-treatment. The Clinical Dementia Rating of AD patients was recorded at these intervals to evaluate treatment efficacy.

RESULTS: Aβ42 levels increased, and Tau protein levels decreased in both groups. The CDR score dropped post treatment. The total effective rate and clinical cure rate were 86.67% and 6.70% in the control group and 100% and 40% in the observation group, respectively. MSCF and MSCs uniquely impact AD.

CONCLUSION: MSCs contributed to damaged nerve cell repair, new nerve cell differentiation, and the participation of some dormant nerve cells in physiological activity. MSCF offered a small-dose, rapid, and safe treatment with simple operation.},
}

@article {pmid42041396,
year = {2026},
author = {Sumbria, RK and Boado, RJ},
title = {Brain Delivery of Antibody-Derived Biologicals for Alzheimer's Disease: An Updated Narrative Review.},
journal = {Antibodies (Basel, Switzerland)},
volume = {15},
number = {2},
pages = {},
doi = {10.3390/antib15020037},
pmid = {42041396},
issn = {2073-4468},
abstract = {Antibodies directed against β-amyloid (Aβ) have been developed for the treatment of Alzheimer's disease (AD). However, the in vivo central efficacy is reduced by the poor penetration of antibodies across the blood-brain barrier (BBB). In addition, these antibodies have been associated with adverse effects like amyloid-related imaging abnormalities. Thus, the development of new antibody-based therapies for AD with improved transport across the BBB may improve efficacy and reduce adverse effects. Antibodies targeting the BBB transferrin receptor (TfR) are able to cross the BBB through receptor-mediated transcytosis, producing a global distribution throughout the brain. Along the same line, bispecific antibodies directed to both the BBB TfR and Aβ showed enhanced brain uptake and pharmacological effects with diminished adverse side effects in experimental animal models of AD and in clinical trials. A generation of brain-penetrating fusion proteins targeting the BBB-TfR has been shown to represent novel treatments for AD, and this includes erythropoietin, tumor necrosis factor alpha inhibitors, neprilysin, somatostatin, oligonucleotides, and an antibody activating TREM2. The aim of this article is to review the progress made in the delivery of antibody-derived biologicals to the brain for AD, targeting the BBB-TfR.},
}

@article {pmid42041587,
year = {2026},
author = {Elias, A and Stern, S},
title = {Gene Editing Strategies for Neurological and Mental Disorders: Advances in Delivery, Methodology, and Clinical Translation.},
journal = {Cells},
volume = {15},
number = {8},
pages = {},
doi = {10.3390/cells15080720},
pmid = {42041587},
issn = {2073-4409},
mesh = {Humans ; *Gene Editing/methods ; *Nervous System Diseases/therapy/genetics ; *Mental Disorders/therapy/genetics ; *Genetic Therapy/methods ; Animals ; CRISPR-Cas Systems/genetics ; *Gene Transfer Techniques ; *Translational Research, Biomedical ; },
abstract = {Neurological and mental disorders are among the main causes of disability worldwide, affecting over three billion people and increasing the socioeconomic burden. Advances in molecular genetics and genome engineering have led to gene-targeted therapies that address root causes rather than just symptoms. This review covers current genome-editing tools, including CRISPR/Cas, base editing, and prime editing. The focus is on the benefits of gene editing in the central nervous system, where post-mitotic neurons allow lasting effects after a single treatment. It also discusses emerging delivery platforms such as viral vectors, nanoparticles, and exosome systems, as well as methods to bypass the blood-brain barrier. Recent clinical progress in spinal muscular atrophy, Parkinson's disease, Huntington's disease, and Alzheimer's disease is highlighted, with promising preclinical results for autism, bipolar disorder, epilepsy, and other neurogenetic conditions. The review concludes with regulatory issues, market trends, and ongoing clinical trials, underscoring the potential of gene therapies to transform disease management and provide long-term solutions.},
}

Humans
*Gene Editing/methods
*Nervous System Diseases/therapy/genetics
*Mental Disorders/therapy/genetics
*Genetic Therapy/methods
Animals
CRISPR-Cas Systems/genetics
*Gene Transfer Techniques
*Translational Research, Biomedical

@article {pmid42042055,
year = {2026},
author = {Jakobović, N and Kalinovčić, P and Borovec, J and Primožič, I and Hrenar, T},
title = {Quantum-Chemical Multiligand Simultaneous Docking of Three-Membered Rings in the Active Site of Butyrylcholinesterase.},
journal = {Current issues in molecular biology},
volume = {48},
number = {4},
pages = {},
doi = {10.3390/cimb48040395},
pmid = {42042055},
issn = {1467-3045},
support = {HRZZ-IP-2022-10-9525//Croatian science foundation/ ; },
abstract = {Alzheimer's disease is a progressive neurodegenerative disorder marked by declining cognitive function. While early-stage treatment focuses on acetylcholinesterase (AChE) inhibition, butyrylcholinesterase (BChE) activity increases as the disease progresses, contributing to cholinergic deficits and neuroinflammation. This shift in enzyme dominance presents a compelling rationale for developing BChE-specific inhibitors as a potential therapeutic avenue. This study explores small, three-membered rings, scaffolds offering potential for interaction with the enzyme's active site, as building blocks for novel BChE inhibitors. Employing a computational approach based on quantum-chemical multiligand simultaneous molecular docking, we virtually fitted these compounds into the BChE active site to predict binding affinity and key interactions. Our calculations extend beyond simple shape matching by incorporating accurate electronic properties, leading to more reliable predictions of binding strength and stability. The goal was not immediate identification of potent inhibitors, but a systematic assessment of how these rings interact with BChE. This foundational knowledge will inform the design and synthesis of larger, more complex molecules with enhanced binding affinity and selectivity, ultimately aiming to develop compounds to inhibit BChE activity and potentially slow Alzheimer's progression.},
}

@article {pmid42042094,
year = {2026},
author = {Allegra, P and Lodico, M and Migliazzo, C and Tarantino, D and Piccoli, T and Vanacore, N and Salemi, G and Maniscalco, L and Matranga, D},
title = {The Need for Standardized Data Collection to Improve Harmonization and Pooling of Information About Modifiable Risk Factors for Alzheimer's Diseases in Italian Clinical Studies: A Systematic Review.},
journal = {Geriatrics (Basel, Switzerland)},
volume = {11},
number = {2},
pages = {},
doi = {10.3390/geriatrics11020038},
pmid = {42042094},
issn = {2308-3417},
support = {"PNRR M6C2- Investimento 2.1 Valorizzazione e potenziamento della ricerca biomedica del SSN", grant number PNRRMAD-2022-12375822, CUP derivato: I75E22000550006-CUP Master ISS I55E22000560006//European Union-Next Generation EU/ ; },
abstract = {BACKGROUND/OBJECTIVES: At the international level, harmonized networks of dementia clinical studies are available, but Italian participation remains limited. This systematic review aims to define harmonization rules to facilitate the inclusion of Italian clinical studies in existing networks and to propose standardized data collection methods to enable comparison of the study results.

METHODS: A systematic review was conducted (January 2019-December 2024) to identify Italian clinical studies evaluating Alzheimer's disease and other dementias as outcomes. Eight modifiable risk factors were extracted: BMI, arterial hypertension, diabetes, dietary patterns, alcohol consumption, smoking habits, depressive symptomatology, and physical activity. WHO definitions and internationally accepted criteria were used as reference standards. Variable harmonization potential was assessed using the DataSHaPER methodology and classified as complete, partial, or impossible, considering information loss across studies.

RESULTS: Of 365 records identified, 18 studies met the inclusion criteria. Obesity assessed via BMI showed the highest harmonization potential (44% complete, 33% partial), along with dietary habits measured by food frequency questionnaires (44% complete). Diabetes and physical inactivity followed (33% complete), assessed through fasting glucose or pharmacological treatment and the IPAQ, respectively. Smoking habits classified as current, former, or never smokers were reported in 28% of studies. Depression (assessed by GDS or CES-D) and hypertension (blood pressure measurement or antihypertensive treatment) showed complete harmonization in only 22% of studies.

CONCLUSIONS: Italian studies show substantial limitations in the harmonization of modifiable risk factor data for Alzheimer's disease, mainly due to heterogeneous and non-standardized data collection methods, highlighting the need for uniform research protocols.},
}

@article {pmid42042095,
year = {2026},
author = {Durrani, S and Mussawar, M and Alaverdashvili, M},
title = {Impact of Comprehensive Geriatric Assessments on Dementia Care.},
journal = {Geriatrics (Basel, Switzerland)},
volume = {11},
number = {2},
pages = {},
doi = {10.3390/geriatrics11020039},
pmid = {42042095},
issn = {2308-3417},
abstract = {Introduction: According to the Alzheimer Society of Canada, over 770,000 people in Canada are living with dementia. This number is expected to rise to nearly 1 million people by 2030. Although the provision of team-based interprofessional assessment in gerontological care is critical for the early detection and prevention of dementia, its planning and delivery can be a challenge. In Saskatchewan, previous assessments have identified significant gaps between actual and best practices in dealing with this medical condition. The emergence of Geriatric Services Resource Teams (GSRTs), which apply an innovative, team-based model to improve the diagnosis and care of older adults with complex health practices, can be proven beneficial in this regard. The purpose of this study is to compare the efficacy of the care provision process between a GSRT and a traditional medical care channel (i.e., primary health) with respect to dementia patients. Methods: A retrospective patient chart review was conducted by collecting data from a large Primary Care practice (n = 90) and the GSRT in Regina (n = 75). Collected data included information on patient demographics and treatment, and the diagnosis process itself. Results: While demographic characteristics between patient groups were similar, significant differences (p < 0.05) were found in the involvement of pharmacy and other healthcare professionals, prescriptions for memory loss, and in who made the diagnosis. Moreover, although the dementia diagnosis was usually made first in Primary Care, further clarification of the type of dementia, counseling of diagnosis, review of medication, and assessment of functions and social supports were better managed in the GSRT group. Discussion: The use of Geriatric Services Resource Teams is a relatively new concept in Saskatchewan. As these teams are established, initial results show that their role in complex care management has beneficial outcomes for dementia patients.},
}

@article {pmid42042200,
year = {2026},
author = {Xu, ZH and Zou, ZB and Wang, CX and Li, C and Yang, XW and Wang, JS},
title = {Anti-Neuroinflammatory Naphtho-γ-Pyrones from a Deep-Sea-Derived Fungus Aspergillus niger 3A00562.},
journal = {Marine drugs},
volume = {24},
number = {4},
pages = {},
doi = {10.3390/md24040125},
pmid = {42042200},
issn = {1660-3397},
support = {22177143//National Natural Science Foundation of China/ ; },
mesh = {Animals ; Zebrafish ; *Pyrones/pharmacology/chemistry/isolation & purification ; *Aspergillus niger/chemistry ; *Anti-Inflammatory Agents/pharmacology/chemistry/isolation & purification ; Molecular Docking Simulation ; Alzheimer Disease/drug therapy ; Mice ; Oxidative Stress/drug effects ; Nitric Oxide Synthase Type II/metabolism ; Disease Models, Animal ; Microglia/drug effects ; Cell Line ; Aquatic Organisms ; Inflammation/drug therapy ; Reactive Oxygen Species/metabolism ; },
abstract = {Inhibition of inflammation and oxidative stress is increasingly recognized as a promising therapeutic strategy for neurodegenerative diseases. In this study, we isolated two new dimeric naphtho-γ-pyrone (aS)-fonsecinones B and D (1 and 2) and 14 known compounds (3-16) from the deep-sea-derived fungus Aspergillus niger 3A00562. Their structures were unambiguously determined through integrated physicochemical and spectroscopic analyses. Screening for neuroinflammatory inhibitors using a BV2 microglial cell model identified TMC 256 A1 (10) as the most potent candidate. Compound 10 significantly suppressed LPS-induced inflammation in BV2 cells without cytotoxicity. It concurrently inhibited LPS-triggered ROS overproduction and neutrophilic infiltration in zebrafish. Subsequent proteomics revealed that 10 targets NOS2 to modulate Alzheimer's disease (AD)-associated pathways and the KEAP1-NRF2 axis. Molecular docking and dynamics simulations demonstrated that 10 occupies the NOS2 heme-binding pocket, thereby preventing dimerization and inhibiting enzymatic activity. Finally, 10 ameliorated locomotor deficits in an AD zebrafish model. Collectively, these findings highlight compound 10 as a candidate compound for preventing inflammatory and oxidative stress damage during treatment of neurodegenerative diseases, particularly AD.},
}

Animals
Zebrafish
*Pyrones/pharmacology/chemistry/isolation & purification
*Aspergillus niger/chemistry
*Anti-Inflammatory Agents/pharmacology/chemistry/isolation & purification
Molecular Docking Simulation
Alzheimer Disease/drug therapy
Mice
Oxidative Stress/drug effects
Nitric Oxide Synthase Type II/metabolism
Disease Models, Animal
Microglia/drug effects
Cell Line
Aquatic Organisms
Inflammation/drug therapy
Reactive Oxygen Species/metabolism

@article {pmid42042246,
year = {2026},
author = {Abdullah, and Fatima, Z and Ruiz, MJT and Espinosa-Sosa, O and Sánchez-Mejorada, CG and Téllez, RQ and Rodríguez, JLO and Sidorov, G},
title = {Explainable Patient-Level Cognitive Impairment Screening via Temporal, Semantic, and Psycholinguistic Multimodal AI.},
journal = {Journal of Intelligence},
volume = {14},
number = {4},
pages = {},
doi = {10.3390/jintelligence14040066},
pmid = {42042246},
issn = {2079-3200},
abstract = {Early diagnosis of cognitive decline is vital for timely treatment of mild cognitive impairment (MCI) and Alzheimer's disease (AD), yet standard clinical assessments often miss subtle longitudinal language changes. We propose a hierarchical hybrid intelligence framework integrating long-context language modeling, temporal progression, semantic graph reasoning, psycholinguistic biomarkers, and contrastive progression learning to classify patient states (Normal, MCI, AD) from longitudinal electronic health record (EHR) notes. The model was trained on 4500 patients and 68,000 clinical notes from Medical Information Mart for Intensive Care III (MIMIC-III) and externally validated on the Medical Information Mart for Intensive Care IV (MIMIC-IV) clinical notes dataset (5200 patients, 72,000 notes). Inputs combined Biomedical and Clinical Bidirectional Encoder Representations from Transformers (BioClinicalBERT) embeddings, Bidirectional Long Short-Term Memory (Bi-LSTM) temporal encodings, Graph Sample and Aggregate (GraphSAGE)-based Unified Medical Language System (UMLS) concept graphs, and psycholinguistic vectors (lexical diversity, grammatical complexity, discourse coherence). On the MIMIC-III hold-out set, the model achieved 99.999% accuracy, a macro F1-score of 0.999, a Receiver Operating Characteristic Area Under the Curve (ROC AUC) of 0.999, and a temporal stability variance of 0.0008. Monte Carlo cross-validation (10,000 folds) yielded 99.997±0.003% accuracy and 0.999±0.001 macro F1. Feature ablation confirmed distinct gains from temporal, semantic, and psycholinguistic modules, improving performance by 1.1% over text-only baselines. Cross-cohort zero-shot testing on MIMIC-IV showed strong generalization with minimal decline in macro F1 and balanced accuracy. Explainability analyses, such as SHapley Additive exPlanations (SHAP) token/concept attribution, attention maps, counterfactual perturbations, and psycholinguistic importance, revealed clinically interpretable markers, such as pronoun overuse, reduced lexical diversity, and syntactic simplification, as predictors of decline. Our framework supports scalable, non-invasive early screening in a variety of healthcare settings by providing longitudinally stable predictions.},
}

@article {pmid42043712,
year = {2026},
author = {Khozani, MS and Palizvan, M and Mosayebi, G and Ganji, A and Ghazavi, A},
title = {Chitosan-curcumin nanoparticles: a potential nano-therapeutic for cognitive restoration in a streptozotocin-induced rat model of Alzheimer's disease.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {42043712},
issn = {1568-5608},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and memory impairment, with no definitive cure currently available. Neuroinflammation, oxidative stress, and amyloid-beta accumulation play central roles in disease progression. While curcumin shows therapeutic promise, its clinical efficacy is limited due to poor bioavailability. This study investigates the neuroprotective effects of chitosan-curcumin nanoparticles in a streptozotocin (STZ)-induced rat model of AD, focusing on cognitive performance, hippocampal integrity, and molecular markers of neurodegeneration.

METHODS: Sixty male Wistar rats were randomly divided into five groups: control, AD, AD + chitosan, AD + curcumin, and AD + chitosan-curcumin. AD was induced via intraventricular injection of STZ (3 mg/kg). Two weeks' post-induction, cognitive function was assessed using the Morris water maze (MWM). At the end of the treatment period, oxidative stress parameters, inflammatory cytokines, and gene expression levels (IL-1β, IL-6, IL-10, NRF2, PPARγ, BDNF) were measured via real-time PCR. Data were analyzed using one-way ANOVA with Tukey's post hoc test (p < 0.05).

RESULTS: Rats treated with chitosan-curcumin nanoparticles exhibited significantly improved memory and learning compared to all other groups (p < 0.001). There was a marked downregulation of IL-1β and IL-6, along with increased expression of NRF2, PPARγ, and BDNF (p < 0.05). Histological analysis confirmed reduced neuronal damage and increased neuronal density. Chitosan-curcumin nanoparticles demonstrated potent neuroprotective effects, enhancing cognitive performance, reducing inflammation and oxidative stress, and preserving neuronal structure.

CONCLUSION: These multifaceted effects highlight the therapeutic potential of CS-CUR nanoparticles in targeting the core pathological mechanisms of AD. Future studies should focus on long-term safety and efficacy assessments, dose-response optimization, and mechanistic pathway analyses to further elucidate the neuroprotective actions of CS-CUR nanoparticles. Additionally, translational and clinical investigations are warranted to validate the therapeutic potential of this nanocarrier system for Alzheimer's disease management.},
}

@article {pmid42043831,
year = {2026},
author = {Farrell, C and Saini, F and Beidas, MM and Ryan, NS and Strydom, A and Wiseman, FK},
title = {Use of anti-amyloid-β monoclonal antibodies in persons with Down syndrome Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71404},
doi = {10.1002/alz.71404},
pmid = {42043831},
issn = {1552-5279},
support = {UKDRI-1211//UK Dementia Research Institute through UK DRI Ltd, principally funded by the UK Medical Research Council/ ; UKDRI-1010//UK Dementia Research Institute through UK DRI Ltd, principally funded by the UK Medical Research Council/ ; UKDRI-TAP23∖12//UK Dementia Research Institute through UK DRI Ltd, principally funded by the UK Medical Research Council/ ; AS-PhD-19a-007/ALZS_/Alzheimer's Society/United Kingdom ; MB2020∖100003//Rosetrees Trust/ ; 2021B#2083//the Jérôme Lejeune Foundation/ ; MR/S011277/1/MRC_/Medical Research Council/United Kingdom ; MR/S005145/1/MRC_/Medical Research Council/United Kingdom ; MR/R024901/1/MRC_/Medical Research Council/United Kingdom ; //National Institute for Health and Care Research/ ; //NIHR University College London Hospitals Biomedical Research Centre (BRC), NIHR Maudsley BRC/ ; //UCL Neurogenetic Therapies Programme/ ; //funded by the Sigrid Rausing Trust/ ; NC/S001298/1/NC3RS_/National Centre for the Replacement, Refinement and Reduction of Animals in Research/United Kingdom ; ARUK-SRF2018A-001//Alzheimer's Research UK/ ; ARUK-SRFEXT2022-001//Alzheimer's Research UK/ ; },
mesh = {Humans ; *Down Syndrome/complications ; *Alzheimer Disease/drug therapy/complications/immunology ; *Amyloid beta-Peptides/immunology ; *Antibodies, Monoclonal/therapeutic use ; Blood-Brain Barrier ; Antibodies, Monoclonal, Humanized/therapeutic use ; },
abstract = {INTRODUCTION: The recent development and licensing of anti-amyloid-β monoclonal antibodies for the treatment of early-stage Alzheimer's disease have significantly shifted the clinical landscape. However, current use recommendations preclude the administration of these new drugs to persons who have Down syndrome.

METHODS: This narrative review considers the ethical and biological factors relating to the administration of anti-amyloid-β monoclonal antibody therapies to persons who have Down syndrome. Literature was selected based on relevance.

RESULTS: Here, we discuss the current understanding of Down syndrome Alzheimer's disease, and how this informs potential benefits and risks of treatment with anti-amyloid-β monoclonal antibodies.

DISCUSSION: The blood-brain barrier and immune system differ in persons with Down syndrome, and cerebral amyloid angiopathy is elevated compared to late-onset Alzheimer's disease. Thus, side-effect risks from anti-amyloid-β monoclonal antibodies are likely to be elevated. Further research is needed to facilitate the treatment of persons with Down syndrome with these new therapies.},
}

Humans
*Down Syndrome/complications
*Alzheimer Disease/drug therapy/complications/immunology
*Amyloid beta-Peptides/immunology
*Antibodies, Monoclonal/therapeutic use
Blood-Brain Barrier
Antibodies, Monoclonal, Humanized/therapeutic use

@article {pmid42043884,
year = {2026},
author = {Bonpandi, E and John, C and Arumugam, P},
title = {Synthesis, structural elucidation, DNA binding, cleavage, cholinesterase inhibitory activity of metal complexes of novel 2,2'-bipyridyl derivative.},
journal = {Nucleosides, nucleotides & nucleic acids},
volume = {},
number = {},
pages = {1-34},
doi = {10.1080/15257770.2026.2659226},
pmid = {42043884},
issn = {1532-2335},
abstract = {To achieve efficient cholinesterase inhibitory activity of metal(II) complexes of Cu(II), Ni(II), Co(II), and Zn(II) with 2,2'-bipyridyl framework [M-L] (L = 2,2'-bipyridyl derivative containing an aromatic center and an e[-]-withdrawing -NO2 group) was developed. The structural characteristics were identified through spectroscopic and analytical studies. The antibacterial activity of the produced ligand and metal(II) complexes against bacteria and fungi was evaluated. The synthesized metal(II) complexes ability to fragment DNA has been studied on pUC 18 DNA using agarose gel electrophoresis. The copper(II) complex (Kb=4.11 × 10[5] M[-1]) is stronger binding affinity for DNA than ethidium bromide (EB) (Kb=3.3 × 10[5] M[-1]) and metal(II) complexes. The chemically produced 2,2'-bipyridyl derivative had the strongest inhibitory effects against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) with IC50 values that were less than the standard compounds (0.34 and 3.42 µM, respectively). Our research results could aid in the creation of novel drug molecules, especially for the treatment of neurological conditions like Alzheimer's disease and neurological disorders occurring through diabetes.},
}

@article {pmid42043894,
year = {2026},
author = {Dendooven, A and Vandendriessche, A and Koshy, PJ and Timmermans, F and Speeckaert, M and Kint, N and Van Aelst, L and Vekemans, MC and Meuleman, N and Pouleur, AC and Bondue, A and Droogmans, S and Debonnaire, P and De Bleecker, J and Van Craenenbroeck, A and Gallardo, R and Schymkowitz, J and Rousseau, F and Impens, F and Devos, S and Delforge, M},
title = {Belgian recommendations for tissue diagnosis of amyloidosis.},
journal = {Acta clinica Belgica},
volume = {},
number = {},
pages = {1-14},
doi = {10.1080/17843286.2026.2660739},
pmid = {42043894},
issn = {2295-3337},
abstract = {BACKGROUND: Amyloidosis is a disorder caused by the extracellular deposition of misfolded protein fibrils, leading to organ dysfunction. Diagnosis remains challenging due to non-specific clinical presentations and the diversity of amyloid subtypes. Accurate identification of the amyloid precursor protein is key for prognostication and treatment strategy.

OBJECTIVES: This document aims to provide practical recommendations for the tissue diagnosis of amyloidosis within the Belgian healthcare context. It targets clinicians managing amyloidosis patients and pathologists evaluating biopsies with suspected amyloid deposits.

METHODS: A structured PubMed search ('amyloidosis AND biopsy AND stain*'; 'amyloidosis AND mass spectro*') was conducted in August 2025. After exclusion of case reports, preclinical studies, and Alzheimer-related articles, 298 publications were reviewed. Recommendations were formulated based on available evidence and discussed among Belgian clinical and pathology experts.

RESULTS: Key recommendations emphasize that tissue biopsies remain essential for amyloidosis diagnosis and typing. Congo red staining with birefringence and fluorescence confirmation is required. Immunohistochemistry and immunofluorescence are first-line subtyping tools, while mass spectrometry serves as a reference method when results remain inconclusive. Centralization of complex analyses in experienced centres is encouraged.

CONCLUSIONS: These recommendations promote standardized, early and accurate tissue diagnosis of amyloidosis in Belgium, supporting optimal patient management and harmonization of diagnostic practices across institutions.},
}

@article {pmid42030370,
year = {2026},
author = {Panda, SR and Soni, U and Panja, P and Rajdev, B and Singh, M and Kundu, S and Ranade, A and Pawar, SD and Acharya, R and Naidu, VGM},
title = {Modulation of Mitochondrial Dynamics by Loganic Acid Ameliorates Alzheimer's Disease Pathology: Evidence from In Vitro and In Vivo Studies.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.6c00012},
pmid = {42030370},
issn = {1948-7193},
abstract = {Alzheimer's disease (AD) is the most common neurodegenerative disorder in the elderly, which refers to forgetting facts and experiences. Apart from being a classical neuropathological hallmark, AD is connected with pronounced mitochondrial fragmentation, although the exact contribution of mitochondrial dynamics in AD progression is poorly defined. Therefore, this study is aimed at investigating the role of loganic acid (LGA) in mitochondrial dynamics, hippocampal plasticity, and cognitive deficits in the scopolamine (SC)-induced cognitive impairment model. The results showed significant decline of p-Drp1 protein and elevation of Mfn2 proteins in LGA-treated SC-induced mice, indicating reduced mitochondrial fragmentation and restoration of mitochondrial dynamics. In addition, LGA treatment promotes the reduction of fragmented and spherical-shaped mitochondria in SC-induced mice. LGA treatment alleviated reactive oxygen species (ROS) production and elevated mitochondrial membrane potential, reducing neurodegeneration in SC mice. Moreover, the decline of inflammatory cytokines (TNF-α and IL-1β) and downregulation of NF-kB expression in LGA-treated SC-induced mice suggested improved neuronal health. In parallel, LGA also increased the regulation of the cytoskeleton within neuronal dendrites, synaptic plasticity, and neuronal dendrites outgrowth, which was validated with increased expression of MAP2. In conclusion, the present study findings suggest that LGA exerts neuroprotection via preserving the mitochondrial ultrastructure and modulating the mitochondrial dynamics. All of these changes further restore neuronal cell density and myelination, leading to the mitigation of neurodegeneration, and restore cognitive deficits and spatial memory in SC-induced C57BL/6 mice.},
}

@article {pmid42031084,
year = {2026},
author = {Hernández, A and Illán, IA and Ramírez, J and Segovia, F and Martínez-Murcia, FJ and Levin, J and Górriz, JM and , },
title = {Robust validation of neuroimaging and clinical models via the SAR method: A case study based on the ADNI dataset.},
journal = {NeuroImage},
volume = {333},
number = {},
pages = {121917},
doi = {10.1016/j.neuroimage.2026.121917},
pmid = {42031084},
issn = {1095-9572},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and substantial brain atrophy. Early and accurate prediction of disease progression and staging is crucial for timely intervention and effective treatment planning. Previous studies, including those based on artificial intelligence techniques, have employed neuroimaging, biomarkers and clinical data to model AD progression; however, many of these approaches rely on strong parametric assumptions or lack robust statistical guarantees regarding model validity. To bridge this gap, this study proposes a novel framework for validating predictive and staging models of disease using a statistically agnostic methodology. The objective is to take the advantages of an unconventional method for robust validation of ML models related to AD. Validation is performed using the Statistical Agnostic Regression (SAR) methodology applied to the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset. The method tests for a linear relationship by resampling and estimating an upper bound on the expected risk (R) via a Bayesian bound under the worst-case scenario. The SAR power assesses the likelihood of detecting a true linear relationship using the test statistic R, via Monte Carlo simulations under the null distribution. Three predictive models related to structural neuroimaging are assessed: one for the Mini Mental State Examination (MMSE) score, another for the concentration of amyloid beta 1-42 protein in the cerebrospinal fluid, and a third for age. In addition, a model for staging based on Alzheimer's-related clinical groups is explored through the joint analysis of segmented gray matter and white matter images. The findings indicate that the SAR methodology not only facilitates robust validation of predictive ML models related to neuroimaging and AD but also enables an effective staging of the AD continuum. This SAR-proposed framework opens new perspectives for the validation of ML models for early diagnosis and provides a solid foundation for future research in computational neuroscience.},
}

@article {pmid42033099,
year = {2026},
author = {Luo, QH and Li, F and Yang, L and Pan, HQ and Zhu, WP and Hu, P and Tao, CM and Yin, M and Zhang, S and Liao, QY and Chen, ZH and Shu, HX and Zhu, XY and Yan, TF and Liu, X and Tu, JL and Zhu, XG},
title = {Endothelial NAD[+] depletion drives vascular senescence and neuroinflammation via mtDNA-cGAS/STING-CD38 signaling in Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71423},
pmid = {42033099},
issn = {1552-5279},
support = {82501463//National Natural Science Foundation of China/ ; 82260278//National Natural Science Foundation of China/ ; 20232BAB216047//Jiangxi Provincial Natural Science Foundation/ ; 20242BAB25478//Jiangxi Provincial Natural Science Foundation/ ; 20242BAB26136//Jiangxi Provincial Natural Science Foundation/ ; 20242BAB20383//Jiangxi Provincial Natural Science Foundation/ ; 2023M741521//China Postdoctoral Science Foundation/ ; },
mesh = {Animals ; *NAD/deficiency/metabolism ; *Alzheimer Disease/metabolism/pathology ; Mice ; *DNA, Mitochondrial/metabolism ; Signal Transduction ; *Endothelial Cells/metabolism ; *Nucleotidyltransferases/metabolism ; Membrane Proteins/metabolism ; *Neuroinflammatory Diseases/metabolism ; Mice, Transgenic ; Cellular Senescence ; Humans ; Disease Models, Animal ; Mitochondria/metabolism ; STING Protein ; Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase ; Niacinamide/analogs & derivatives ; Pyridinium Compounds ; },
abstract = {BACKGROUND: Endothelial dysfunction has emerged as early and pivotal event in Alzheimer's disease (AD), yet the molecular mechanisms linking vascular aging to neuroinflammation remain elusive.

METHODS: We used APP/PS1 mice and amyloid beta (Aβ)-challenged brain endothelial cells (BECs) to understand the mechanisms of nicotinamide adenine dinucleotide (NAD[+]) deficiency, and its relationship with endothelial senescence and neuroinflammation in AD pathology. Nicotinamide riboside supplementation was administered to APP/PS1 mice to determine whether restoration of NAD[+] homeostasis mitigates AD-related vascular and inflammatory pathology.

RESULTS: NAD[+] deficiency induced voltage-dependent anion channel 1 (VDAC1) oligomerization, mitochondrial DNA (mtDNA) leakage, and cGAS/STING-IRF3 activation, promoting endothelial senescence and SASP production with NAD[+]-consuming enzyme CD38 upregulation. Senescent BECs triggered IL-6-dependent microglial activation. NR treatment restored mitochondrial integrity, suppressed cGAS-STING signaling, and reduced neuroinflammation, improving vascular function and cognition.

DISCUSSION: Aβ-driven NAD[+] deficiency initiates a VDAC1-mtDNA-cGAS/STING cascade that promotes endothelial senescence and neurovascular inflammation in AD pathology, and amplifies neuroinflammation through BEC-microglia crosstalk, highlighting NAD[+] restoration as a promising AD therapeutic strategy.},
}

Animals
*NAD/deficiency/metabolism
*Alzheimer Disease/metabolism/pathology
Mice
*DNA, Mitochondrial/metabolism
Signal Transduction
*Endothelial Cells/metabolism
*Nucleotidyltransferases/metabolism
Membrane Proteins/metabolism
*Neuroinflammatory Diseases/metabolism
Mice, Transgenic
Cellular Senescence
Humans
Disease Models, Animal
Mitochondria/metabolism
STING Protein
Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
Niacinamide/analogs & derivatives
Pyridinium Compounds

@article {pmid42033410,
year = {2026},
author = {Gu, X and Terebuh, P and Xu, R and Kaelber, DC and Davis, PB},
title = {Age-related macular degeneration and dementia: Association through pathogenesis or visual impairment?.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261438849},
doi = {10.1177/13872877261438849},
pmid = {42033410},
issn = {1875-8908},
abstract = {BackgroundStudies suggest a link between blindness, age-related macular degeneration (AMD), and dementia risk, but whether this stems from AMD pathology or blindness remains unclear. This study examines the relationship between AMD and dementia.ObjectiveTo evaluate the association between AMD and 5-year dementia risk in non-blind patients.MethodsThis retrospective cohort study used TriNetX to compare non-blind patients with exudative AMD (n = 35,021) and non-exudative AMD (n = 96,809) to those without AMD (n = 1,801,879) for five-year dementia risk. Blind (n = 90,615) and non-blind (n = 800,737) patients were compared. Cohorts were propensity-matched for confounding factors.ResultsNon-blind AMD patients had decreased Alzheimer's disease risk, while blindness showed a strong positive association. Exudative AMD had HR of 0.84 (95% CI = [0.72, 0.97]), non-exudative AMD had HR of 0.95 (95% CI = [0.87, 1.04]), but blindness increased Alzheimer's disease risk (95% HR = 1.29, CI = [1.17, 1.41]).ConclusionsThese findings suggest that previously reported associations between AMD and dementia may be partially mediated by visual impairment. The modest reduction in dementia risk in non-blind AMD patients may reflect differences in healthcare utilization or treatment exposure among AMD patients.},
}

@article {pmid42033565,
year = {2026},
author = {Ishii, K},
title = {Brain PET in the era of anti-amyloid-β antibody therapy for Alzheimer disease.},
journal = {Japanese journal of radiology},
volume = {},
number = {},
pages = {},
pmid = {42033565},
issn = {1867-108X},
abstract = {Here the current and emerging roles of brain positron emission tomography (PET) in Alzheimer's disease (AD) in the era of anti-amyloid-β antibody therapy, with a focus on clinical applications, methodological considerations, and future perspectives were reviewed. A narrative review of the literature on PET imaging in AD, including FDG-PET, amyloid PET, and tau PET, was conducted with particular emphasis on their clinical utility in diagnosis, and disease monitoring. Relevant guidelines, including appropriate use criteria and Japanese clinical guidelines, were also reviewed. FDG-PET provides valuable information for the differential diagnosis of neurodegenerative dementias based on characteristic hypometabolic patterns, although its role remains supportive due to the lack of direct assessment of molecular pathology. Amyloid PET enables noninvasive visualization of cerebral amyloid-β deposition and has become essential for confirming eligibility for anti-amyloid therapies. Standardized use criteria and interpretation guidelines are critical for appropriate clinical implementation. Quantitative approaches, such as standardized uptake value ratios (SUVRs) and the Centiloid scale, improve comparability across studies and institutions. Tau PET reflects neurofibrillary pathology and correlates with disease severity and progression, with increasing relevance for patient stratification. In addition, recent advances in high-resolution dedicated brain PET systems and artificial intelligence-based image analysis are expected to enhance diagnostic performance and workflow efficiency. In the era of disease-modifying therapy, brain PET imaging has become integral to the clinical management of AD. Amyloid PET is indispensable for treatment eligibility, while tau PET provides complementary information on disease stage and prognosis. Ongoing technological and methodological advancements will further expand the role of PET imaging in precision medicine for dementia.},
}

@article {pmid42028071,
year = {2026},
author = {Sun, X and Yang, L and Wang, X},
title = {Traditional Chinese Medicine for Alzheimer's Disease: Current Evidence and Chemometric Approaches for Multi-Target Evaluation.},
journal = {Neuropsychiatric disease and treatment},
volume = {22},
number = {},
pages = {590661},
pmid = {42028071},
issn = {1176-6328},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder for which there is currently no therapy that can fundamentally change the disease course. The limitations of single-target drugs have led the scientific community to turn to multi-target intervention strategies. In this context, traditional Chinese medicine (TCM) demonstrates potential in addressing the complex pathology of AD due to its "multi-component, multi-target, multi-pathway" overall regulatory characteristics. This review systematically reviews the current research status of TCM in the treatment of AD, with a particular focus on the evidence of its effects through multiple mechanisms such as reducing Aβ deposition, inhibiting excessive phosphorylation of Tau protein, regulating the cholinergic system, and alleviating neuroinflammation. Additionally, this article highlights how to utilize the "spectral efficacy relationship" combined with chemometrics methods (such as multiple regression, partial least squares regression, artificial neural networks, etc) to establish quantitative correlations between TCM chemical components and efficacy/clinical endpoints, thereby providing a methodological framework for evaluating the synergistic effects of TCM's multi-component interactions. The article also summarizes the evidence grades of currently commonly used TCM preparations in clinical practice and points out that future research needs to continuously deepen in areas such as standardized clinical endpoints, strict trial design, systematic safety assessment, and data-driven efficacy analysis. This review aims to provide theoretical references and research directions for integrating the holistic view of TCM with modern system analysis methods and promoting the development of multi-target treatment strategies for AD.},
}

@article {pmid42025825,
year = {2026},
author = {Liu, S and Yang, C and Zhang, N and Xiang, L and Li, F and Qi, L and Xu, X},
title = {AXL prevents amyloid-β-induced microglial ferroptosis by sustaining SLC2A3-mediated mitochondrial respiration.},
journal = {Pharmacological research},
volume = {},
number = {},
pages = {108203},
doi = {10.1016/j.phrs.2026.108203},
pmid = {42025825},
issn = {1096-1186},
abstract = {Dysregulated iron metabolism is a pivotal driver of Alzheimer's disease (AD). Excess iron promotes Aβ aggregation and tau hyperphosphorylation, thereby accelerating disease progression. Serving as the primary iron reservoir in the central nervous system, microglia are intrinsically susceptible to ferroptosis, thereby amplifying neurotoxicity to neighboring neurons. While plaque-associated receptors (e.g., TREM2, AXL, MERTK) govern microglial responses, their precise contribution to metabolic susceptibility to ferroptosis remains elusive. Here, we identify the receptor tyrosine kinase AXL as a critical metabolic safeguard against Aβ-induced ferroptosis in microglia. Mechanistically, our findings indicate that, under our experimental conditions, oAβ exposure is associated with downregulation of AXL in microglia, thereby impairing SLC2A3-dependent glucose uptake and mitochondrial ATP production, which ultimately increases ferroptotic vulnerability. Moreover, through an optimized surface plasmon resonance imaging (SPRi) screening approach, we identified the FDA-approved drug levothyroxine (L-T4) as a potent AXL agonist. L-T4 treatment restores microglial homeostasis, inhibits Aβ-induced ferroptosis, and ameliorates neuropathology in vivo. These findings establish AXL as a novel metabolic safeguard in microglia and highlight L-T4 as a promising therapeutic strategy for AD and other ferroptosis-related disorders via drug repurposing.},
}

@article {pmid42025961,
year = {2026},
author = {Hajibandeh, S and Tao, YA and Hsieh, MH and Liu, HG and Cheng, YF and Lee, KH and Hsieh, SY and Lu, CH},
title = {Semaglutide for obesity management: A narrative review of efficacy, safety, and future directions.},
journal = {Journal of the American Pharmacists Association : JAPhA},
volume = {},
number = {},
pages = {103117},
doi = {10.1016/j.japh.2026.103117},
pmid = {42025961},
issn = {1544-3450},
abstract = {BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), particularly semaglutide, have demonstrated substantial efficacy for glycemic control and weight management and are increasingly prescribed across diverse populations. Rapid expansion of indications, formulations, and real-world use has outpaced comprehensive evaluation of long-term safety, tolerability, and adherence, raising important concerns for clinical practice.

OBJECTIVES: This narrative review aims to synthesize current evidence on the efficacy and safety profile of semaglutide, with a focus on adverse events, treatment persistence, perioperative considerations, and use in special populations, to support clinical decision-making and pharmacist-led patient care.

METHODS: A review of clinical trials, observational studies, pharmacovigilance reports, regulatory communications, and professional guidelines was conducted. Evidence was drawn from randomized controlled trials, post-marketing safety reports, systematic reviews, and relevant clinical and regulatory documents.

RESULTS: From 1525 records, 34 studies and reports were included. Clinical trials consistently demonstrated meaningful weight reduction with semaglutide. Evidence regarding acute pancreatitis remains limited, although cases have been reported in clinical trials and postmarketing safety analyses. Evidence regarding suicidal ideation associated with semaglutide is mixed, with some analyses suggesting potential safety signals while others report no increased risk. Recent multi society clinical guidelines have addressed perioperative management of GLP-1 RAs, generally supporting individualized perioperative assessment. Emerging literature also examines semaglutide use in special populations, including patients with Alzheimer disease and individuals following bariatric surgery, although long-term neurologic and post-bariatric safety outcomes remain incompletely characterized.

CONCLUSIONS: Semaglutide represents an important therapeutic option for chronic weight management. As clinical use expands, continued evaluation of long-term safety, tolerability, and treatment persistence will be important. Pharmacists play a key role in counseling patients, monitoring adverse effects, supporting adherence, and contributing to multidisciplinary obesity care.},
}

@article {pmid42026254,
year = {2026},
author = {Nakagawa, T and Xie, JL and Park, K and Cao, K and Savadkohighodjanaki, M and Zhang, YJ and Jun, H and Ichii, A and Lee, JY and Soma, S and Medhat, YK and Saido, TC and Igarashi, KM},
title = {Early dopamine disruption in the entorhinal cortex of a knock-in model of Alzheimer's disease.},
journal = {Nature neuroscience},
volume = {},
number = {},
pages = {},
pmid = {42026254},
issn = {1546-1726},
support = {A2019380S//BrightFocus Foundation (BrightFocus)/ ; A2022018F//BrightFocus Foundation (BrightFocus)/ ; BRFSG-2017-04//Brain Research Foundation (BRF)/ ; JPMJPR2481//MEXT | Japan Science and Technology Agency (JST)/ ; AARF-22-923955/ALZ/Alzheimer's Association/United States ; },
abstract = {The entorhinal cortex is a critical brain area for memory formation, while also the region exhibiting the earliest histological and functional alterations in Alzheimer's disease (AD). The entorhinal cortex therefore has been long hypothesized as one of the originating brain areas of AD pathophysiology, although circuit mechanisms causing its selective vulnerability remain poorly understood. Here we show that dopamine neurons projecting their axons to the lateral entorhinal cortex (LEC), critical for memory formation in healthy brains, become dysfunctional from the early pathological stage and cause associative memory impairments in amyloid precursor protein knock-in mice. Dopamine dysfunction led to the disruption of associative memory encoding of LEC layer 2/3. Optogenetic reactivation of LEC dopamine fibers rescued associative learning behavior. L-DOPA treatment restored memory encoding of LEC neurons and associative memory of amyloid precursor protein knock-in mice. These results suggest early dysfunction of LEC-projecting dopamine neurons underlie memory impairment in AD from early stages, pointing to a need for clinical investigation of LEC dopamine in patients with AD.},
}

@article {pmid42026868,
year = {2026},
author = {Huang, J and Wang, YB and Wu, J and Qian, PJ and Shao, J and Cao, DD and Liu, Y and Luo, ZG},
title = {SEC62-mediated ER-Phagy activation alleviates Alzheimer's disease pathology and restores cognitive function in 5×FAD mice.},
journal = {Molecular therapy : the journal of the American Society of Gene Therapy},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.ymthe.2026.04.037},
pmid = {42026868},
issn = {1525-0024},
abstract = {Alzheimer's disease (AD) is a common age-related neurodegenerative disorder. Previous studies have shown that patients with AD exhibit dysregulation of endoplasmic reticulum (ER) homeostasis in the brain, such as ER stress and ER damage. As a type of selective autophagy that specifically clears damaged ER, ER-phagy (endoplasmic reticulum-phagy) plays a key role in ER quality control, but the role in AD progression remains elusive. In this study, we found that ER homeostasis is severely disrupted in the pathological state of AD, characterized by enhanced ER stress response, the presence of ER damage, and concurrent defects in ER-phagy function. Notably, some receptors mediating ER-phagy were decreased in neurons differentiated from induced pluripotent stem cells (iPSCs) derived from AD patients and in 5×FAD mouse samples. Interestingly, overexpression of the ER-phagy receptor SEC62 in the brain of 5×FAD mice via intrathecal AAV injection markedly alleviated disease phenotypes, including β-amyloid (Aβ) plaque deposition, neuroinflammation, and cognitive impairment. These results indicate that restoring ER-phagy activity provides a potential strategy for the treatment of AD.},
}

@article {pmid41840370,
year = {2026},
author = {Gönüllü, S and Aydın, Ş and Çelik, H and Çelik, O and Küçükler, S and Topal, A and Akay, R and Yıldız, MO and Alım, B and Özdemir, S},
title = {Milk-derived miR-126-3p-loaded small extracellular vesicles attenuate amyloid-β-induced cellular stress in a neuroblastoma cell model.},
journal = {BMC neuroscience},
volume = {27},
number = {1},
pages = {},
pmid = {41840370},
issn = {1471-2202},
abstract = {UNLABELLED: Alzheimer’s disease (AD) is characterized by progressive neurodegeneration driven by amyloid-β (Aβ)–associated oxidative stress, mitochondrial dysfunction, and dysregulated inflammatory signaling. Although microRNAs (miRNAs) represent promising regulators of these interconnected pathways, their therapeutic application is limited by instability and inefficient cellular delivery. In this study, the cytoprotective potential of milk-derived small extracellular vesicles (sEVs) loaded with miR-126-3p was evaluated in an Aβ-induced SH-SY5Y neuroblastoma cell model. sEVs were isolated and characterized according to MISEV guidelines, loaded with synthetic miR-126-3p, and administered to Aβ-induced cells. miR-126-3p–enriched sEVs significantly attenuated Aβ-induced oxidative stress, as evidenced by normalization of ROS, LDH, GPX1, MDA, and SOD levels, while naïve sEVs exerted only partial effects. At the transcriptional level, miR-126-3p delivery restored stress-responsive gene expression patterns by reducing ICAM1 and TNF-α expression and normalizing BDNF levels, reflecting modulation of neuron-intrinsic inflammatory signaling rather than tissue-level neuroinflammation. Markers of cytoskeletal and mitochondrial stress, including intracellular NfL, cytochrome c, 8-OHdG, TFAM, PINK1, and DNM1L, were also significantly reduced following miR-126-3p–loaded sEV treatment, indicating improved cellular homeostasis under amyloid stress. Furthermore, intracellular tau-related markers and Aβ1–40 accumulation were attenuated, consistent with suppression of Aβ-triggered pathological signaling cascades. Collectively, these findings demonstrate that sEV-mediated miR-126-3p delivery confers robust cytoprotective effects at the cellular level in a neuroblastoma model. While extrapolation to in vivo neurodegeneration requires caution, the results highlight milk-derived sEVs as a biocompatible and scalable platform for miRNA-based modulation of AD-relevant cellular stress pathways.

GRAPHICAL ABSTRACT: [Image: see text]},
}

@article {pmid42020180,
year = {2026},
author = {Tong, FF and Huang, RQ and Gao, Y and Luo, QQ and Chen, YP and Xu, GZ},
title = {[Epidemiological studies of the association between dyslipidemia and Alzheimer's disease].},
journal = {Zhonghua liu xing bing xue za zhi = Zhonghua liuxingbingxue zazhi},
volume = {47},
number = {4},
pages = {767-774},
doi = {10.3760/cma.j.cn112338-20250727-00528},
pmid = {42020180},
issn = {0254-6450},
mesh = {*Alzheimer Disease/epidemiology ; Humans ; *Dyslipidemias/epidemiology/complications ; Risk Factors ; },
abstract = {Alzheimer's disease (AD), as the representative type of dementia among neurodegenerative diseases, has become a major challenge in the field of global public health. Dyslipidemia is considered an acquired risk factor for AD, and both are progressive diseases with long developmental periods, making dyslipidemia a potential predictor of future AD occurrence. Therefore, preventing dyslipidemia is of great significance for the prevention and treatment of AD. Given the global epidemiological background of AD, this article aims to systematically review the association between dyslipidemia and AD, providing theoretical support for the prevention and control of both conditions.},
}

*Alzheimer Disease/epidemiology
Humans
*Dyslipidemias/epidemiology/complications
Risk Factors

@article {pmid42020356,
year = {2026},
author = {Zou, Z and Chen, J and Li, J and Chen, Y},
title = {The iron-energy metabolism axis in Alzheimer's pathogenesis: from mechanisms to interventions.},
journal = {Cell death discovery},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41420-026-03034-w},
pmid = {42020356},
issn = {2058-7716},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder with a complex, multifactorial pathogenesis. Growing evidence implicates disturbances in cellular energy metabolism and iron dyshomeostasis as interlinked contributors to pathology. Within this framework, iron accumulation may act as an upstream regulator in certain contexts and stages, while in others it emerges downstream and amplifies ongoing injury. As iron is an essential cofactor for mitochondrial respiration and the tricarboxylic acid cycle, iron imbalance can compromise ATP production and disrupt glucose metabolism, exacerbating neuronal energy deficits. The interplay among iron accumulation, oxidative stress, and neuroinflammation can create vicious cycles that reprogram cellular metabolism and disrupt the critical metabolic coupling between neurons and glial cells. This review synthesizes recent advances in understanding the iron-energy metabolism axis in AD, delineates mechanisms by which iron imbalance precipitates mitochondrial dysfunction and glucose metabolic impairments, and evaluates how these deficits synergize with neuroinflammation and proteinopathy across disease stages. Finally, we appraise emerging therapeutic strategies targeting iron overload and metabolic pathways, discuss their stage-dependent risks and benefits, and outline the need for biomarker-guided approaches to optimize patient selection and treatment timing.},
}

@article {pmid42020790,
year = {2026},
author = {Ferreira, AFF and Feng, ZP and Sun, HS and Britto, LRG},
title = {Inhibiting the transient receptor potential melastatin 2 channel in microglia: current evidence and therapeutic potential in neurological disorders.},
journal = {Acta pharmacologica Sinica},
volume = {},
number = {},
pages = {},
pmid = {42020790},
issn = {1745-7254},
abstract = {Microglia, the resident immune cells of the central nervous system, play a pivotal role in neuroinflammation and is a key contributor to the onset and progression of various neurological and neurodegenerative diseases. The Transient Receptor Potential Melastatin 2 (TRPM2), a non-selective calcium channel, has emerged as a sensor linking oxidative stress responses and calcium influx. It is expressed in many tissues and cells, including neurons, astrocytes, and microglia. TRPM2 represents one of the molecular mediators regulating microglial activity and function, cytokine production, and microglia-neuron communication. Growing evidence suggests that TRPM2 contributes to the pathological mechanisms underlying diseases such as ischemic stroke, Alzheimer's disease, Parkinson's disease, epilepsy, and neuropathic pain. However, most of the studies mainly explored the TRPM2 involvement in cell death, which has been reviewed by some other authors. In this review, we compile and discuss findings from in vivo and in vitro studies evaluating the role of TRPM2, with a specific focus on its influence over microglial function and neuroinflammatory responses, a field that has been poorly explored. We gathered information from studies reporting, in stroke models, that both pharmacological inhibition and genetic deletion of TRPM2 reduced infarct volume, improved behavioral outcomes, and diminished glial reactivity. In models of neurodegeneration, TRPM2 modulation shows promising effects on neuronal survival and microglial phenotype. In neuropathic pain models, TRPM2 was found to mediate microglial activation and the release of pro-inflammatory mediators, contributing to pain hypersensitivity. However, findings in epilepsy models reveal a more complex picture, with TRPM2 deficiency producing either neuroprotective or deleterious outcomes, highlighting the need for further studies. Although most studies to date support a pathogenic role for TRPM2 in microglia-mediated neuroinflammation, some limitations were highlighted, as the non-selective pharmacological inhibitors available, the inclusion of only males in the majority of studies, and the use of a global TRPM2 knockout. Only two studies employed conditional genetic models to promote specific TRPM2 deletion from microglia, with promising findings. Overall, current evidence indicates TRPM2 as a promising modulator of microglia, with broad implications for the treatment of neurological disorders characterized by chronic inflammation.},
}

@article {pmid42021568,
year = {2026},
author = {Li, Z and Ge, R and Zhao, Z and Xiao, H and Du, C and Lai, Y and Wang, L},
title = {From Bio-Interface Materials to Neural Integration: The Next-Generation Brain-Machine Interfaces Powered by Hydrogels.},
journal = {Advanced materials (Deerfield Beach, Fla.)},
volume = {},
number = {},
pages = {e23422},
doi = {10.1002/adma.202523422},
pmid = {42021568},
issn = {1521-4095},
support = {22322803//National Natural Science Foundation of China/ ; 22375047//National Natural Science Foundation of China/ ; 22361162607//International Cooperation and Exchanges NSFC/ ; 20240305028YY//Key Research Development Program of Jilin Province/ ; 2022YFB3804905//National Key Research and Development Program of China/ ; 2022YFB3804900//National Key Research and Development Program of China/ ; //Graduate Innovation Fund of Jilin University/ ; FZ2025038//State Key Laboratory of New Textile Materials and Advanced Pro- cessing/ ; },
abstract = {Brain-machine interfaces (BMIs), which serve as revolutionary tools for neural recording, modulation, and rehabilitation, are highly dependent on the biocompatibility and mechanical suitability of their electrode materials. Although traditional metal electrodes possess excellent conductivity, their inherent rigidity causes a substantial mechanical mismatch with soft neural tissue, leading to chronic inflammatory responses and poor long-term stability. The emergence of hydrogel electrodes has provided a breakthrough solution to this fundamental limitation. Hydrogels, characterized by their softness, high ionic conductivity, and tissue-like compliance, offer a viable solution to mitigate these issues. This review systematically explores the material properties of hydrogel-integrated BMIs, providing an in-depth investigation of key hydrogel characteristics, including toughness, adhesion, conductivity, and biocompatibility. Additionally, hydrogel-based BMIs are categorized into non-invasive and invasive systems, each defined by its characteristic operational principles and signal-acquisition mechanisms. The study further reviews critical issues, including surgical implantation strategies, multimodal data fusion, integration of artificial intelligence, as well as system integration and clinical translation. From a therapeutic perspective, this work highlights the application of BMIs in treating neurological disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, stroke, neuropathic pain, and depression. Furthermore, this review critically examines the persistent challenges faced by hydrogel-based BMIs and proposes innovative strategies for future development. Ultimately, it outlines a developmental roadmap for next-generation hydrogel-based biotherapeutic technologies aimed at achieving high-fidelity, stable and clinically translatable BMI systems.},
}

@article {pmid42021966,
year = {2026},
author = {Tabi, YA and Meyer, EC},
title = {Autoimmune diseases are associated with increased neurodegenerative and cerebrovascular risk, while systemic corticosteroid exposure shows limited neurodegenerative and modest vascular associations.},
journal = {IBRO neuroscience reports},
volume = {20},
number = {},
pages = {596-608},
pmid = {42021966},
issn = {2667-2421},
abstract = {Systemic autoimmune diseases (AIDs), characterized by chronic peripheral inflammation and frequent vascular comorbidity, are increasingly linked to adverse central nervous system (CNS) outcomes; however, comparative evidence across diverse AIDs and clarification of the roles of vascular burden, inflammatory activity, and immunomodulatory therapy remain limited. Using the TriNetX Global Collaborative Network, we conducted a sequence of retrospective, propensity score-matched cohort experiments in adults aged 50-85 years to quantify incident Parkinson's disease (PD), Alzheimer's disease (AD), transient ischemic attack (TIA), and ischemic stroke across 22 AIDs and to evaluate therapy- and inflammation-stratified risk patterns. In the primary disease-control analysis (Experiment 1 A), AID diagnosis was associated with broadly elevated neurodegenerative and cerebrovascular risk, with stronger and more consistent associations for TIA and ischemic stroke than for PD and AD. To probe robustness, we repeated analyses under tighter control of baseline vascular burden (Experiment 1B: additional matching on circulatory-system diagnoses) and under treatment balancing (Experiment 1 C: additional matching on immune-suppressant exposure). Vascular matching substantially attenuated many associations, particularly for AD, whereas immune-suppressant matching did not materially erase the pervasive cerebrovascular excess. Within-disease CRP stratification (Experiment 2; low vs elevated CRP) did not yield a uniform neurodegenerative gradient but identified a disease-dependent ischemic vulnerability axis in selected inflammatory phenotypes. In treatment substudies, systemic cortisone exposure (Experiment 3) showed little association with PD/AD risk but a modest, heterogeneous increase in TIA/ischemic stroke. Medication-specific strata (Experiment 4) revealed stronger but directionally variable separations, consistent with confounding by indication and severity. Together, these findings position systemic autoimmunity as a robust marker of heightened cerebrovascular risk and a more phenotype-dependent correlate of neurodegenerative risk, supporting intensified vascular surveillance in high-risk AID populations and mechanistic work disentangling inflammation, comorbidity, and treatment.},
}

@article {pmid42022334,
year = {2026},
author = {Bhagunde, P and Penner, N and Willis, BA and Bell, R and Sachdev, P and Charil, A and Irizarry, MC and Hersch, S and Reyderman, L},
title = {Pharmacokinetic/pharmacodynamic analyses of plasma pathophysiology biomarkers in subjects with early Alzheimer's disease following lecanemab treatment.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {},
pages = {e70246},
pmid = {42022334},
issn = {2352-8737},
abstract = {INTRODUCTION: Lecanemab, a novel monoclonal antibody targeting both neurotoxic amyloid beta (Aβ) protofibrils and Aβ plaques, substantially reduces markers of amyloid and significantly slows clinical decline on multiple measures of cognition and function in early AD in Phase 2 (Study 201) and Phase 3 (Study 301; Clarity AD) studies. In these clinical studies, several plasma biomarkers showed improvements comparing lecanemab with placebo. Herein, we utilized modeling and simulation to evaluate the long-term effects of lecanemab on pathophysiology biomarkers in plasma.

METHODS: Plasma Aβ42/40 ratio, tau phosphorylated at threonine 181 (p-tau181), and glial fibrillary acidic protein (GFAP) data were pooled from lecanemab Phase 2 and 3 studies. Individual serum lecanemab exposure estimated using a population pharmacokinetic model was correlated with plasma biomarker concentrations using indirect response pharmacokinetic/pharmacodynamic (PK/PD) models. Simulations were conducted to evaluate the effect of lecanemab (10 mg/kg IV every 2 weeks, LEC10-BW) after 4 years of continuous treatment, discontinuation after 18 months of treatment or transitioning to less frequent dosing at 18, 24, or 30 months.

RESULTS: PK/PD models describing the change in plasma biomarker levels over time in response to lecanemab treatment were developed, and simulations demonstrated that plasma biomarkers reverted toward pretreatment baseline after cessation of lecanemab treatment, with an average re-accumulation half-life of approximately 1 to 1.5 years, which was faster than amyloid plaque re-accumulation measured by positron emission tomography. Simulations illustrated transitioning to a lecanemab monthly dosing regimen was sufficient to stabilize plasma biomarker concentrations at levels consistent with ongoing inhibition of amyloid pathology and neuroinflammation.

DISCUSSION: PK/PD model simulations demonstrated that plasma biomarkers serve as early indicators of amyloid accumulation and downstream effects. Plasma biomarker simulations suggest the need for ongoing lecanemab treatment even after amyloid plaque clearance. Transition to a less frequent monthly IV regimen at 18 months was shown to maintain the changes in plasma biomarker levels consistent with lecanemab efficacy.},
}

@article {pmid42022743,
year = {2026},
author = {Dai, D and Chen, J and Guo, X and Sun, J and Yi, H},
title = {Mechanistic research on the vestibular-hippocampal pathway in neurodegenerative diseases: an integrative perspective from molecular to behavioral levels.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1779268},
pmid = {42022743},
issn = {1662-4548},
abstract = {This paper systematically reviews the pivotal role and bidirectional regulatory mechanisms of the Vestibular-hippocampal pathway in the onset and progression of neurodegenerative diseases (such as Alzheimer's disease), focusing on the common comorbidity of vestibular dysfunction and cognitive decline. Evidence spanning molecular to behavioral levels indicates that vestibular signal loss can induce hippocampal atrophy and spatial memory impairment through neuroinflammation, impaired synaptic plasticity, and disrupted theta rhythms. Conversely, hippocampal degeneration further impairs vestibular information integration, creating a vicious cycle. Intervention approaches such as vestibular rehabilitation, cognitive training, and neurostimulation show potential for slowing co-morbidity progression. Future research should focus on developing animal models simulating vestibular-neurodegenerative co-morbidity, conducting longitudinal clinical validation using multimodal imaging and electrophysiology techniques, and optimizing neuromodulation strategies and targeted molecular interventions to advance this mechanism toward early diagnosis and precision treatment.},
}

@article {pmid42022958,
year = {2026},
author = {Chien, SC and Chien, YC and Wang, HJ and Chen, JC},
title = {A ZIF-8-modified electrochemical biosensor for sensitive Aβ aggregation monitoring and Alzheimer's disease drug screening.},
journal = {RSC advances},
volume = {16},
number = {23},
pages = {20855-20865},
pmid = {42022958},
issn = {2046-2069},
abstract = {Alzheimer's disease (AD) is an irreversible neurodegenerative disorder driven by the abnormal aggregation of β-amyloid (Aβ) into oligomers, fibrils, and plaques. Current therapeutic strategies primarily alleviate symptoms but struggle to prevent aggregation due to the dynamic nature of Aβ species and prolonged drug development cycles. Sensitive and real-time monitoring of Aβ structural transitions is therefore essential for understanding disease progression and evaluating potential inhibitors. In this study, we developed a ZIF-8-modified electrochemical biosensor capable of translating Aβ42 conformational changes into quantifiable current signals, providing a promising platform for monitoring dynamic aggregation. The aggregation behavior of Aβ42 was systematically characterized using dynamic light scattering (DLS), electrochemical measurements, and Thioflavin T (ThT) fluorescence combined with ultrafiltration. A critical transition from the lag to the growth phase was observed at 24 h, with aggregates exceeding ∼60 nm undergoing irreversible fibrillization. The ZIF-8-modified electrochemical sensor detected early-stage structural rearrangements with superior sensitivity compared to conventional ThT fluorescence, revealing subtle oligomer formation. Quantitative current measurements allowed continuous monitoring of aggregation kinetics, highlighting the temporal resolution of the platform. Validation experiments with curcumin treatment demonstrated strong inhibitory effects between 18 and 24 h, delaying fibrillization, reducing late-stage β-sheet accumulation, and decreasing aggregate size by approximately 25%. In addition, the sensor successfully distinguished minor differences in structural transitions under varying inhibitor concentrations, demonstrating its capability for high-resolution, real-time assessment of aggregation dynamics and drug efficacy. This ZIF-8-modified electrochemical biosensor provides high-sensitivity, dynamic monitoring of Aβ42 aggregation and drug-induced inhibition, offering a valuable tool for mechanistic studies of protein aggregation pathology. By enabling early detection of structural transitions and real-time evaluation of inhibitors, this platform has the potential to accelerate therapeutic screening and improve the development of effective interventions for AD.},
}

@article {pmid42023276,
year = {2026},
author = {Kuan, JH and Raghavan, RS and Koh, DLW and Tan, WY and Iezhitsa, I and Agarwal, R},
title = {Navigating the cholesterol maze: Key insights on use of statins in neurodegenerative disorders.},
journal = {Neuroprotection (Chichester, England)},
volume = {4},
number = {1},
pages = {30-47},
pmid = {42023276},
issn = {2770-730X},
abstract = {Neurodegenerative diseases such as Alzheimer's (AD), Parkinson's (PD), Huntington's (HD), and multiple sclerosis (MS) involve progressive neuronal loss driven by dysregulated neurotransmission, neuroinflammation, oxidative stress, and mitochondrial dysfunction. Cholesterol metabolism has emerged as a critical factor involved with both central and peripheral dysregulation contributing to pathology. This review synthesizes current evidence on cholesterol's role in neurodegeneration and evaluates the therapeutic potential of statins, which act via cholesterol-dependent and other pleiotropic mechanisms. A PubMed search covering 1985-2025 publications was conducted using terms related to neurodegenerative diseases, statins, cholesterol metabolism, neuroinflammation, oxidative stress, mitochondrial dysfunction, and neuroprotection. Studies were selected to highlight mechanistic insights into cholesterol regulation in the nervous system and clinical data on statin use. Neuronal loss in neurodegeneration is driven by processes including excitotoxicity, inflammation, and mitochondrial dysfunction. Excessive reactive oxygen species activate apoptotic pathways involving BAX, BAK, and p53. Dysregulated cholesterol metabolism is a significant contributor: In AD, the ApoE allele ε4 (ApoE4) links elevated cholesterol to amyloid-β (Aβ) accumulation and cognitive decline; in PD, cholesterol shows mixed effects, with some studies suggesting protection and others linking high levels to α-synuclein aggregation and mitochondrial impairment. In HD reduced cholesterol biosynthesis correlates with neuronal loss, while MS associates with elevated cholesterol and cognitive dysfunction. Statins, widely used cholesterol-lowering agents, reduce Aβ production, enhance its clearance, and improve synaptic function. Beyond lipid lowering, they exert anti-inflammatory, antioxidant, and anti-apoptotic effects. Clinical outcomes remain mixed, with benefits influenced by statin type, dose, treatment duration, disease stage, and patient genetics. Statins show multifaceted neuroprotective potential through cholesterol-dependent and independent pathways. While preclinical data are encouraging, clinical evidence is heterogeneous. Long-term, stratified trials are needed to clarify efficacy, and tailoring therapy to disease-specific mechanisms may offer a viable strategy for mitigating neurodegeneration and enhancing neuronal survival.},
}

@article {pmid42023629,
year = {2026},
author = {Li, Y and Li, S and Ma, J and Zhao, J and Ning, N and Sun, J},
title = {The role of synaptic plasticity in Alzheimer's disease: from molecular mechanisms to therapeutic targets.},
journal = {Folia neuropathologica},
volume = {64},
number = {1},
pages = {1-11},
doi = {10.5114/fn.2025.156508},
pmid = {42023629},
issn = {1509-572X},
mesh = {*Alzheimer Disease/physiopathology/pathology/metabolism/therapy ; Humans ; *Neuronal Plasticity/physiology ; Animals ; tau Proteins/metabolism ; Amyloid beta-Peptides/metabolism ; },
abstract = {Alzheimer's disease (AD) is characterized by a complex pathophysiology, involving abnormal aggregation of amyloid b (Ab) and tau proteins, neuroinflammatory responses, and significant synaptic dysfunction, which collectively contribute to cognitive decline. This review offers a novel perspective by focusing on the pivotal role of synaptic plasticity in the pathogenesis of AD, underscoring its potential as a therapeutic target. The study uniquely synthesizes current molecular and clinical research to illustrate how Ab and tau pathologies disrupt synaptic signaling and structure, further exacerbated by neuroinflammation. We explore both pharmacological interventions, such as BACE1 inhibitors and tau stabilizers, and non-pharmacological strategies, including cognitive therapy and neuromodulation techniques, which have shown promise in modulating synaptic plasticity and slowing cognitive deterioration. Despite these advancements, the field faces significant challenges, including the complexity of AD's underlying mechanisms and limitations in early diagnosis. This review not only highlights the significance of synaptic plasticity in AD but also proposes future research directions that could lead to innovative therapeutic approaches, offering new hope for effective treatment strategies.},
}

*Alzheimer Disease/physiopathology/pathology/metabolism/therapy
Humans
*Neuronal Plasticity/physiology
Animals
tau Proteins/metabolism
Amyloid beta-Peptides/metabolism

@article {pmid42024020,
year = {2026},
author = {Chun, H and Lee, HW and Hong, SB and Ha, SS and Yoon, KJ},
title = {Home-based transcranial photobiomodulation improves cognitive function in mild cognitive impairment due to Alzheimer's disease: A randomized, double-blind, placebo-controlled confirmatory trial.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261443973},
doi = {10.1177/13872877261443973},
pmid = {42024020},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is a progressive neurodegenerative disorder in which early bioenergetic dysfunction is increasingly implicated in its pathogenesis. Transcranial photobiomodulation (tPBM), a non-invasive neuromodulation using near-infrared light, has shown promise in improving cerebral metabolism and cognitive function.ObjectiveTo assess the safety and efficacy of a home-administered tPBM intervention in individuals with mild cognitive impairment (MCI) due to AD.MethodsIn this randomized clinical trial, 80 participants meeting the NIA-AA criteria for MCI due to AD were recruited. Participants self-administered a tPBM device emitting 808 nm near-infrared light over the bilateral dorsolateral prefrontal cortex, six times weekly for 12 weeks. The primary outcome was the change in MoCA-K score from baseline to week 13. Secondary outcomes included K-MMSE2, CERAD-K, and GDepS scores.ResultsActive tPBM significantly improved cognitive performance compared with the placebo. Mean MoCA-K scores increased by 3.87 ± 2.51 points in the active group versus a 0.74 ± 2.85 point decline in the placebo group (p < 0.001). K-MMSE2 scores improved significantly (p < 0.001). CERAD-K showed a significant between-group difference at week 13 (p < 0.001), while GDepS scores remained unchanged. No device-related adverse events occurred, and adherence to home-based treatment was high.Conclusions12 weeks of home-administered tPBM safely and significantly improved cognitive function in individuals with MCI due to AD. The observed benefits are consistent with enhanced mitochondrial metabolism, cerebral perfusion, and synaptic efficiency. These findings support tPBM as a promising, non-pharmacological treatment for MCI due to AD and as a preventative strategy against AD.Trial RegistrationKorean Clinical Research Information Service (CRiS), https://cris.nih.go.kr, KCT0011155.},
}

@article {pmid42024084,
year = {2026},
author = {Xie, M and Niu, X and Sun, F and Shi, L},
title = {Transcriptome-based identification and experimental validation of a key gene in Alzheimer's disease using dermal fibroblasts.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261443968},
doi = {10.1177/13872877261443968},
pmid = {42024084},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is a neurodegenerative disorder primarily characterized by progressive cognitive impairment and neuronal damage. The pathogenesis of AD is complex and involves multiple pathological processes. Currently, effective methods for early diagnosis and treatment are lacking.ObjectiveTo identify key pathogenic genes and investigate their roles in Alzheimer's disease, we analyzed transcriptomic data from dermal fibroblasts of AD patients, aiming to assess their potential as novel biomarkers and therapeutic targets.MethodsTranscriptomic data from AD patient and control-derived dermal fibroblasts (DFs) were analyzed to identify differentially expressed genes. Key genes were screened using bioinformatics and a random forest algorithm. ceRNA analysis was performed to explore miRNA-mRNA interactions. The candidate gene SRSF5 was validated via overexpression and knockdown, followed by qPCR, western blotting, and reactive oxygen species (ROS) assays. The role of SRSF5 in endoplasmic reticulum (ER) stress was evaluated by measuring ER stress markers and cellular stress responses.ResultsTranscriptomic analysis revealed significant upregulation of SRSF5 in AD DFs. ceRNA analysis identified miRNAs regulating SRSF5 in AD. Overexpression of SRSF5 led to reduced neuronal proliferation, increased apoptosis, elevated ROS levels, and activation of ER stress markers (CHOP, GRP78, XBP1). SRSF5 knockdown alleviated these effects.ConclusionsSRSF5 may drive AD pathogenesis via ER and oxidative stress, serving as a potential biomarker and therapeutic target for early diagnosis and intervention.},
}

@article {pmid42024119,
year = {2026},
author = {Shan, A and Xu, C and Chen, R and Han, X and Sun, W and Yao, Q and Wang, X and Luan, H and Li, S and Wen, B and Cui, T and Guo, J and Lian, Q and Sun, Y and Li, C and Jia, H and Ma, H and Lv, S and Sun, Q and Wei, C},
title = {Alterations in choroid plexus volume associated with butylphthalide treatment in mild cognitive impairment: Data from a randomized, placebo-controlled study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261443718},
doi = {10.1177/13872877261443718},
pmid = {42024119},
issn = {1875-8908},
abstract = {BackgroundThe choroid plexus (ChP) is increasingly recognized as an essential component in the pathogenesis of cognitive impairment associated with Alzheimer's disease. DL-3-n-butylphthalide (NBP) has been confirmed to exert neuroprotective effects through multiple pathways and thereby enhance cognitive function. However, the role of NBP in the ChP volume remains unclear at present.ObjectiveThis trial aimed to explore the clinical efficacy of NBP in patients with mild cognitive impairment (MCI) and its corresponding ChP imaging characteristics.MethodsThis randomized, double-masked, placebo-controlled study included 270 MCI patients, randomly assigned in a 1:1 ratio to receive either NBP or placebo. Concurrently, all participants received clinical cognitive evaluations and 3D T1-weighted magnetic resonance imaging scans at both baseline and post-treatment phases. The objective was to evaluate the efficacy of 12-month NBP treatment on cognitive impairment and investigate the neuroimaging correlates of NBP therapy, focusing specifically on longitudinal alterations in ChP.ResultsThe NBP treatment significantly improved the cognitive symptoms of MCI patients, which was strongly correlated with the decrease in ChP volume in the drug group. Moreover, subgroup analysis indicated that cognitive enhancement was closely related to changes in ChP volume in the effective group. Mediation effect analysis revealed that ChP volume partially mediated the enhancement of cognitive symptoms in MCI patients undergoing NBP treatment.ConclusionsThis research provided evidence that NBP may improve cognitive symptoms in MCI patients by regulating changes in ChP volume, as well as offered insight into identifying early neuroimaging markers of MCI and drug targets for NBP.Clinical trial registry nameEfficacy and safety of butylphthalide on patients with mild cognitive impairment; Registration number: ChiCTR1800018362.},
}

@article {pmid42024241,
year = {2026},
author = {Alım, Z and Demir, Y},
title = {Evaluation of pyrimidine-based compounds as AChE and BChE inhibitors: in vitro inhibition, molecular modeling, and statistical evaluation.},
journal = {Naunyn-Schmiedeberg's archives of pharmacology},
volume = {},
number = {},
pages = {},
pmid = {42024241},
issn = {1432-1912},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disease characterized by dementia, particularly in older adults. It is a process that is increasing significantly with the aging population worldwide, has yet to be cured, and therefore challenges healthcare systems. The ability of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors to modulate neurotransmitter levels has made AChE/BChE inhibitors central therapeutic targets in drug development studies for the treatment of AD. Previous studies have demonstrated the beneficial effects of pyrimidine derivatives on cognitive functions and highlighted their high therapeutic potential against neurodegenerative diseases. Considering the pharmacological importance of AChE/BChE inhibitors and pyrimidine derivatives, this study investigated the inhibitory potential of seven different pyrimidine derivatives (1-7) on AChE and BChE using both in vitro and in silico approaches. Analysis of IC50 values indicated that compounds 1-7 (IC50: 14.89-77.70 nM) exhibited strong inhibitory effect. Compound 6 (IC50:14.89 nM) had the strongest inhibitory effect on AChE, while it showed a much weaker inhibitory effect against BChE (IC50: 357 nM), corresponding to an approximately 24-fold selectivity for AChE. Molecular modeling results indicate that compounds 6 and 7 exhibit favorable interactions within the active site of the enzyme. In addition, compounds 1 and 3, which exhibited the strongest inhibitory effects on BChE, appear to display a multiple binding profile with the active site of BChE. Correlation and regression analyses indicated that compounds 1-7 display a structure-activity relationship (SAR) consistent with strong inhibitory potency toward AChE, while showing comparatively weaker inhibition toward BChE.},
}

@article {pmid42024486,
year = {2026},
author = {Liu, X and Liu, J and Wang, PY and Cui, JH and Bu, YM and Wu, SS and Zhang, YH and Guo, C},
title = {Parthenolide Ameliorates Alzheimer's Disease Pathology by Suppressing Microglial Inflammation and Inflammation-Driven Amyloidogenesis via the HIF1α/NF-κB Axis.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.6c00141},
pmid = {42024486},
issn = {1948-7193},
abstract = {The treatment landscape for Alzheimer's disease (AD) faces challenges such as prolonged drug development, high costs, and limited FDA-approved therapies. Given the pathological similarities between Early-Onset AD (EOAD) and Late-Onset AD (LOAD), repurposing existing drugs offers a promising strategy to expedite therapeutic development. In this study, weighted gene coexpression network analysis (WGCNA) was applied to identify AD-associated gene modules, followed by network pharmacology to screen candidate compounds. Parthenolide was selected based on blood-brain barrier permeability and disease relevance. Its effects were evaluated using LPS-stimulated BV2 microglia, N2a-sw and HT22 neuronal models, and transgenic AD mouse models. Transcriptomic integration, transcription factor enrichment, pharmacological inhibition, and in vivo behavioral and pathological analyses were employed to elucidate underlying mechanisms. Our findings reveal that parthenolide markedly suppressed microglial activation and reduced pro-inflammatory mediators via modulation of the HIF1α/NF-κB signaling axis. Bioinformatics analysis identified HIF1α as a key hub gene, which was experimentally validated using the selective inhibitor YC-1. Parthenolide attenuated inflammation-induced amyloidogenesis by downregulating amyloid β precursor protein (APP) expression and the γ-secretase component Aph-1A γ-Secretase Subunit (APH1α). In vivo, parthenolide administration significantly improved cognitive performance, reduced microglial activation, decreased β-amyloid plaque burden, and suppressed HIF1α/NF-κB-dependent inflammatory signaling in 5 × FAD mouse models. In conclusion, this study demonstrates that parthenolide exerts multitarget therapeutic effects in AD by concurrently suppressing neuroinflammation and amyloidogenic processing. Targeting the HIF1α/NF-κB axis may represent a promising strategy for modulating inflammatory-metabolic-amyloid networks in AD.},
}

@article {pmid42024924,
year = {2026},
author = {Choo, M and Oh, Y and Hong, LS and Scheitler, KM and Tang-Cabrera, J and Shin, J and Blaha, CD and Shin, H and Park, S and Lee, KH},
title = {Deep Brain Stimulation: Past, Present, and Future.},
journal = {IEEE transactions on bio-medical engineering},
volume = {PP},
number = {},
pages = {},
doi = {10.1109/TBME.2026.3686882},
pmid = {42024924},
issn = {1558-2531},
abstract = {Deep brain stimulation (DBS) has emerged as a revolutionary neurosurgical treatment for various movement and psychiatric disorders. Its development, rooted in advances in stereotactic surgery and early thalamotomies, led to its FDA approval for essential tremor (1997) and Parkinson's disease (2002), followed by applications in dystonia, obsessive-compulsive disorder (OCD), and epilepsy. While DBS has proven effective in these domains, research continues to explore its potential for treating conditions like Alzheimer's disease, addiction, and depression. Despite its clinical success, the underlying mechanisms of DBS remain poorly understood, motivating ongoing studies on neural circuitry modulation. Current DBS applications focus on specific brain targets, such as the subthalamic nucleus for Parkinson's and the anterior nucleus of the thalamus for epilepsy, with new targets under investigation for conditions like OCD and chronic pain. Technological advancements in DBS hardware, including rechargeable implants and directional electrodes, have improved patient outcomes by enhancing precision and reducing side effects. Furthermore, innovations in neuroimaging and closed-loop DBS systems are expanding the capabilities of DBS, offering personalized treatments based on real-time neural feedback. This review highlights the historical evolution, current clinical applications, and future directions of DBS as a transformative therapy for neurological and psychiatric disorders.},
}

@article {pmid42024965,
year = {2026},
author = {Irisarri, A and Bellver-Sanchis, A and Choudhary, BS and Mallo-Abreu, A and Labrador, L and Casadesus, G and Pérez, B and Jana, A and Banerjee, DR and Iriepa, I and Isabel Loza, M and Brea, J and Val, C and Pallàs, M and Muñoz-Torrero, D and Griñán-Ferré, C},
title = {Structure-based virtual screening, in vitro and in silico analysis identified novel potent m6A demethylase FTO inhibitors as promising neurotherapeutic agents.},
journal = {European journal of medicinal chemistry},
volume = {312},
number = {},
pages = {118852},
doi = {10.1016/j.ejmech.2026.118852},
pmid = {42024965},
issn = {1768-3254},
abstract = {Dysregulation of the m6A RNA demethylase FTO has been implicated in neurodegeneration, but brain-penetrant, selective inhibitors remain scarce. Here, we used structure-based virtual screening of a CNS-oriented library to identify novel FTO inhibitors and characterized their permeability, selectivity, and pharmacological profiles. Among them, compound VI showed low-micromolar inhibition of human FTO, selectivity over ALKBH5, high PAMPA-BBB permeability, and oral exposure with measurable plasma levels, moderate brain penetration, and CSF detectability. Molecular dynamics simulations confirmed stable binding of VI within the FTO catalytic pocket, consistent with its enzymatic potency and selectivity. In differentiated SH-SY5Y cells, VI protected against Aβ1-42-induced toxicity while increasing global m6A levels and dampening pro-inflammatory gene expression. In SAMP8 mice, chronic oral treatment with VI (3 mg/kg) ameliorated anxiety-like behavior and rescued hippocampal-dependent spatial and recognition memory, concomitant with increased brain m6A and normalization of synaptic and neuroinflammatory markers. Overall, our findings identify compound VI as a selective, brain-penetrant FTO inhibitor with favorable pharmacokinetics and disease-modifying efficacy in a sporadic Alzheimer's disease model, supporting its further development as a neurotherapeutic candidate.},
}

@article {pmid42025718,
year = {2026},
author = {Li, Y and Chen, J},
title = {Lentinan attenuates tau phosphorylation and memory deficits in hTau-overexpressing mice.},
journal = {Brain research},
volume = {},
number = {},
pages = {150340},
doi = {10.1016/j.brainres.2026.150340},
pmid = {42025718},
issn = {1872-6240},
abstract = {BACKGROUND: Lentinan (LNT), a polysaccharide extracted from shiitake mushrooms, has been long used in Asia for improving health. Although LNT injections have been approved for cancer treatment in multiple Asian countries, the potential of LNT in alleviating Alzheimer's disease (AD) pathology and associated cognitive impairments remains poorly understood. Thus, this study aimed to assess the neuroprotective effects of LNT.

METHODS: In vitro tests were performed in HEK 293/tau cells. Moreover, to simulate AD tau pathology, human full-length tau (hTau) expression was induced using adeno-associated virus serotype 2 (AAV2) in C57/BL6 mice. Intragastric LNT administration for 1 month markedly elevated protein phosphatase 2A (PP2A) activity and decreased tau phosphorylation at Ser202/Thr205 (AT8) in AAV2-hTau infected mice.

RESULTS: LNT significantly enhanced cell viability and PP2A activity while reducing tau phosphorylation in HEK 293/tau cells. Furthermore, behavioral tests demonstrated that LNT mitigated cognitive defects induced through hTau overexpression while significantly increasing the expression of synaptic protein expression such as synaptotagmin and synaptophysin.

CONCLUSIONS: Our findings suggest that LNT can prevent AD-like tau hyperphosphorylation by activating PP2A and attenuate AD-like cognitive impairments by restoring synaptic plasticity and synaptogenesis. Therefore, LNT is a potential therapeutic candidate for treating tau-related diseases.},
}

@article {pmid41803285,
year = {2026},
author = {Kalecký, K and Buitrago, L and Alarcon, JM and Singh, A and Bottiglieri, T and Kaddurah-Daouk, R and Hernández, AI},
title = {Fingolimod normalizes metabolic signatures associated with synaptic plasticity and memory in APP/PS1 model: Sphingosine-1-phosphate receptor a therapeutic target for Alzheimer's.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {},
pmid = {41803285},
issn = {2045-2322},
support = {U01AG061359; U19AG063744; 3U19AG063744-04S1; R01AG046171; RF1AG059093; RF1AG058942; RF1AG051550/NH/NIH HHS/United States ; U01AG061359; U19AG063744; 3U19AG063744-04S1; R01AG046171; RF1AG059093; RF1AG058942; RF1AG051550/NH/NIH HHS/United States ; },
abstract = {UNLABELLED: Previously, our metabolomic, transcriptomic, and genomic studies characterized the ceramide/sphingomyelin pathway as a therapeutic target in Alzheimer’s disease, and we demonstrated that FTY720, a sphingosine-1-phospahate receptor modulator approved for treatment of multiple sclerosis, recovers synaptic plasticity and memory in APP/PS1 mice. To further investigate how FTY720 rescues the pathology, we performed metabolomic analysis in brain, plasma, and liver of trained APP/PS1 and wild-type mice. APP/PS1 mice showed area-specific brain disturbances in polyamines, phospholipids, and sphingolipids. Most changes were completely or partially normalized in FTY720-treated subjects, indicating rebalancing the “sphingolipid rheostat”, possibly reactivating phosphatidylethanolamine synthesis via mitochondrial phosphatidylserine decarboxylase pathway, and normalizing polyamine levels that are known to support mitochondrial activity. Synaptic plasticity and memory were rescued, with spermidine synthesis in temporal cortex best corresponding to hippocampal CA3-CA1 plasticity normalization. FTY720 effects, also reflected in other pathways, are consistent with promotion of mitochondrial function, synaptic plasticity, and anti-inflammatory environment, while reducing pro-apoptotic and pro-inflammatory signals. Additional mechanistic studies should validate the contribution of the suggested pathways to the treatment effects.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1038/s41598-026-42518-8.},
}

@article {pmid42013744,
year = {2026},
author = {Zhao, X and Bao, Y and Wan, X and Miao, R and Li, C and Wang, J and Zhang, H and Xiang, Y and Pang, Y and Miao, Z and Tong, M and Shi, X and Wang, H and Gong, P and Zhao, Y and Hou, Y},
title = {Design, synthesis, and evaluation of dual-target inhibitors of acetylcholinesterase (AChE) and soluble epoxide hydrolase (sEH) for the treatment of Alzheimer's disease.},
journal = {European journal of medicinal chemistry},
volume = {312},
number = {},
pages = {118844},
doi = {10.1016/j.ejmech.2026.118844},
pmid = {42013744},
issn = {1768-3254},
abstract = {In this study, a series of tacrine derivatives featuring a triazole linker with sEH fragment were designed, synthesized, and evaluated for Alzheimer's disease treatment. Among them, compound Z43 exhibited best dual inhibitory activity against AChE and sEH (AChE IC50 = 1.7 nM; sEH IC50 = 0.7 nM) and showed low cytotoxicity in HepG2, SMMC7721 and SH-SY5Y cell lines. In addition, Z43 showed high permeability in PAMPA permeability test. Meanwhile, Z43 protected PC12 cells from H2O2-induced toxicity. Moreover, in LPS-induced BV-2 cell inflammation model, Z43 significantly reduced the levels of TNF-α, IL-1β, IL-6 and iNOS. Acute toxicity tests also indicated a favorable safety profile. In the scopolamine-induced AD mice model, Z43 markedly improved learning and memory deficits, which was significantly better than tacrine and EC5026. In summary, compound Z43 shows promising potential for further research.},
}

@article {pmid42014236,
year = {2026},
author = {Corcoran, E and Kettlety, M and Mogul, U and Azah, JN and Cork, SC},
title = {The effects of GLP-1 receptor agonists on Alzheimer's pathophysiology: A systematic review.},
journal = {Molecular and cellular neurosciences},
volume = {},
number = {},
pages = {104091},
doi = {10.1016/j.mcn.2026.104091},
pmid = {42014236},
issn = {1095-9327},
abstract = {BACKGROUND: The incidence of Alzheimer's disease (AD) is increasing globally but there are limited effective therapies available. Recently, evidence has demonstrated a role of GLP-1 receptor (GLP-1R) agonists, commonly used in the treatment of type 2 diabetes, may have therapeutic potential in AD. GLP-1R agonists have exhibited their neuroprotective role by targeting tau hyperphosphorylation and the accumulation of beta-amyloid (Aβ) plaques. This systematic review aims to evaluate the effectiveness of liraglutide, semaglutide, exenatide and dulaglutide on AD pathology with a focus on the key biomarkers: hyperphosphorylated tau and Aβ.

METHODS: A systematic literature search was conducted using PubMed, Embase and Cochrane Library. Inclusion criteria involved pre-clinical and clinical studies investigating the effects of GLP-1 agonists dulaglutide, liraglutide, semaglutide or exenatide on Aβ and tau pathology. Randomised and non-randomised studies were included. Exclusion criteria involved studies evaluating GLP-1R agonists other than those specified.

RESULTS: This review examined thirty preclinical studies investigating the effects of four GLP-1 receptor agonists on Alzheimer's disease pathology, particularly Aβ plaque accumulation and tau hyperphosphorylation. Most studies focused on liraglutide, which consistently reduced both Aβ and tau pathology in animal and cell models. Dulaglutide, although studied less frequently, consistently reduced tau phosphorylation and Aβ accumulation in mouse models while also improving cognitive outcomes. Semaglutide also showed largely positive effects with four studies reporting reduced Aβ or tau pathology, though one study reported no benefit. Two clinical studies were also reviewed. A phase II trial of Exenatide showed reduced plasma Aβ42 in extracellular vesicles but not cognitive benefit. A smaller liraglutide trial demonstrated no reduction in Aβ burden or cognitive change though it preserved brain glucose metabolism. An EXSCEL trial showed significant changes in systemic inflammatory markers. While pre-clinical data has been encouraging, clinical evidence remains limited.

CONCLUSIONS: There is consistent preclinical evidence that GLP-1R agonists are effective in reducing Aβ levels and hyperphosphorylated tau. While the neuroprotective effect in preclinical studies is clear, clinical findings have so far failed to demonstrate an arresting effect on cognitive.

REGISTRATION: PROSPERO CRD420251029748.},
}

@article {pmid42014786,
year = {2026},
author = {Kim, OH and Shin, CH and Cho, MW and Ha, JY and Choung, JJ and Song, DK and Choi, JY and Chang, ES and Lee, HJ and Ku, SK},
title = {Transcranial vibrotactile stimulation enhances hippocampal cholinergic signaling and memory through frequency-dependent mechanotransduction.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-49377-3},
pmid = {42014786},
issn = {2045-2322},
abstract = {Cholinergic dysfunction is a key contributor to cognitive impairment observed in aging and neurodegenerative disorders such as Alzheimer's disease (AD). Although acetylcholinesterase (AChE) inhibitors have been the mainstay of symptomatic treatment for over two decades, their limited efficacy and adverse effects underscore the need for alternative therapeutic approaches. Recent evidence indicates that mechanical stimulation can modulate neuronal and glial signaling through mechanotransduction, suggesting a potential strategy to enhance cognitive function via non-pharmacological means. Here, we developed a head-mounted vibrotactile stimulation system (HVSS) that delivers controlled vibration to the cranium and evaluated its effects in a pharmacological model of acute cholinergic dysfunction induced by scopolamine. To this end, male C57BL/6 mice received scopolamine (1 mg/kg, i.p.; on days 7, 14, and 28) and were exposed to daily vibrotactile stimulation at 20, 40, or 80 Hz for 28 days. Behavioral performance was assessed using passive avoidance and Morris water maze tests, followed by biochemical and histological analyses. HVSS at 40 Hz and 80 Hz significantly improved cognitive performance, enhanced hippocampal cholinergic function, reduced oxidative damage, and upregulated memory-related signaling genes, including BDNF, PI3K, AKt, ERK1/2, CREB, and CAMK4. These findings suggest that high-frequency HVSS improves memory hippocampal cholinergic function via activation of memory-related signaling pathways, highlighting its potential as a safe, non-pharmacological neuromodulatory strategy for cholinergic dysfunction-related cognitive decline.},
}

@article {pmid42015253,
year = {2026},
author = {Reetz, K and Liepelt-Scarfone, I and Häger, A and Flöel, A and Schulz, JB and , },
title = {The best treatment is prevention: prevention of cognitive decline and dementia - current state, gaps and next steps.},
journal = {Neurological research and practice},
volume = {8},
number = {1},
pages = {},
pmid = {42015253},
issn = {2524-3489},
}

@article {pmid42015299,
year = {2026},
author = {Ge, C and Wang, K and Tang, H and Ke, Y and Wang, H and Fu, Q and Xiu, Y and Guo, Y and Jia, YF and Long, Z and He, G and Tang, Q},
title = {NDST3 suppression restores lysosomal acidification and ameliorates amyloid-β and MAPT/tau pathology in Alzheimer's disease.},
journal = {Translational neurodegeneration},
volume = {15},
number = {1},
pages = {},
pmid = {42015299},
issn = {2047-9158},
support = {BJRC202310//Project of the Top-Notch Talent Cultivation Program for the Graduate Students of Chongqing Medical University/ ; W0168//Program for Youth Innovation in Future Medicine, Chongqing Medical University/ ; 82371203//National Natural Science Foundation of China/ ; 82201582//National Natural Science Foundation of China/ ; CSTB2024NSCQ-MSX0483//Natural Science Foundation of Chongqing, China/ ; KJQN202200457//Science and Technology Research Program of Chongqing Municipal Education Commission/ ; },
mesh = {Animals ; *Lysosomes/metabolism/pathology ; *Alzheimer Disease/metabolism/pathology/genetics ; *tau Proteins/metabolism ; Mice ; Humans ; *Amyloid beta-Peptides/metabolism ; Mice, Transgenic ; Histone Deacetylase 6/metabolism ; Hippocampus/metabolism/pathology ; },
abstract = {BACKGROUND: Impairment of lysosomal acidification has recently been identified as a critical driver of amyloid-β and MAPT/tau pathology in Alzheimer's disease (AD). Restoring lysosomal acidification is a promising strategy for AD treatment. N-deacetylase and N-sulfotransferase 3 (NDST3) is a newly discovered tubulin deacetylase that regulates lysosomal acidification by influencing the recruitment of V-ATPase V1 subunits to lysosomes. Nevertheless, the role of NDST3 in AD remains entirely unexplored.

METHODS: We began by comparing the effects of NDST3 and histone deacetylase 6 (HDAC6), a well-known tubulin deacetylase with established roles in AD, on lysosomal acidification. Using HT22 cell-based models of AD, we knocked down NDST3 to examine its role in lysosomal acidification and degradative function in the context of this disease. We also evaluated the expression profile of NDST3 in both in vitro and in vivo models of AD. Finally, we investigated the consequences of NDST3 suppression on lysosomal acidity and related AD pathological features in the hippocampi of 3 × Tg-AD mice.

RESULTS: NDST3 differs from HDAC6 in the subcellular spatial patterns of catalyzing microtubule deacetylation but parallels HDAC6 in regulating lysosomal pH. In HT22 cells with APP695[Swe] overexpression, knockdown of NDST3 lowered lysosomal pH by promoting the assembly of the V-ATPase holoenzyme on the lysosomal membrane and enhanced the autophagic degradation of aberrant Aβ and MAPT/tau. Notably, NDST3 levels were found to be elevated in the brains of AD models and patients. Reducing NDST3 expression in the hippocampi of 3 × Tg-AD mice facilitated lysosomal reacidification, which decreased the abnormal accumulation of amyloid plaques and MAPT/tau tangles, mitigated neuronal damage, and ameliorated cognitive deficits.

CONCLUSIONS: Our study identified NDST3 as a key factor regulating lysosomal acidity in AD. Suppressing NDST3 restores lysosomal function in AD and protects against AD pathology, highlighting NDST3 as a promising therapeutic target for AD.},
}

Animals
*Lysosomes/metabolism/pathology
*Alzheimer Disease/metabolism/pathology/genetics
*tau Proteins/metabolism
Mice
Humans
*Amyloid beta-Peptides/metabolism
Mice, Transgenic
Histone Deacetylase 6/metabolism
Hippocampus/metabolism/pathology

@article {pmid42015324,
year = {2026},
author = {Li, R and Langford, O and Insel, PS and Sperling, RA and Raman, R and Aisen, PS and Donohue, MC},
title = {Divergent patterns of cognitive decline in preclinical Alzheimer's disease: Implications for secondary prevention trials.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71366},
doi = {10.1002/alz.71366},
pmid = {42015324},
issn = {1552-5279},
support = {//Epstein Family Foundation/ ; //Avid Radiopharmaceuticals/ ; //GHR Foundation/ ; //Foundation for the National Institutes of Health/ ; //Eli Lilly and Company/ ; /ALZ/Alzheimer's Association/United States ; U24AG057437/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease ; Male ; Female ; *Cognitive Dysfunction/diagnostic imaging/prevention & control ; Aged ; Positron-Emission Tomography ; tau Proteins/metabolism ; Amyloid beta-Peptides/metabolism ; Longitudinal Studies ; Biomarkers ; *Secondary Prevention ; Disease Progression ; Prodromal Symptoms ; Hippocampus/pathology/diagnostic imaging ; Neuropsychological Tests ; },
abstract = {INTRODUCTION: Biomarkers identify Alzheimer's disease pathology in cognitively unimpaired adults, but the timing and rate of cognitive decline vary widely. This study aimed to identify subgroups of cognitive decline and baseline predictors of heterogeneity in preclinical progression.

METHODS: Data were drawn from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease Study, which enrolled amyloid beta-positive (Aβ+) participants, and the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) Study, which enrolled amyloid beta-negative (Aβ-) individuals. Latent class mixed-effects models identified cognitive trajectory classes. Associations between class membership and demographic, clinical, and biomarker variables were evaluated. The primary outcome was change in the Preclinical Alzheimer Cognitive Composite.

RESULTS: Three trajectory classes were identified: stable, slow decliners, and fast decliners. Higher phosphorylated tau at 217 (p-tau217), smaller hippocampal volume, and elevated tau positron emission tomography were associated with declining classes. About 70% of Aβ+ individuals were stable.

DISCUSSION: Latent class modeling reveals substantial heterogeneity in preclinical trajectories with important implications for prevention trial design.},
}

Humans
*Alzheimer Disease
Male
Female
*Cognitive Dysfunction/diagnostic imaging/prevention & control
Aged
Positron-Emission Tomography
tau Proteins/metabolism
Amyloid beta-Peptides/metabolism
Longitudinal Studies
Biomarkers
*Secondary Prevention
Disease Progression
Prodromal Symptoms
Hippocampus/pathology/diagnostic imaging
Neuropsychological Tests

@article {pmid42015334,
year = {2026},
author = {van Etten, ES and Mahinrad, S and Grill, JD and Salloway, S and Atri, A and Cogswell, PM and Benzinger, TLS and Iwatsubo, T and Iadecola, C and Lemere, CA and Nicoll, JAR and Greenberg, SM and Carrillo, MC and Jack, CR and Sperling, RA},
title = {Amyloid-related imaging abnormalities (ARIA) in anti-amyloid therapies for Alzheimer's disease: An update from the Alzheimer's Association ARIA workgroup.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71361},
doi = {10.1002/alz.71361},
pmid = {42015334},
issn = {1552-5279},
support = {09150162410011/ZONMW_/ZonMw/Netherlands ; 642991//Alzheimer Nederland/ ; R01NS136122/NH/NIH HHS/United States ; R01AG084531/NH/NIH HHS/United States ; P30AG066519/NH/NIH HHS/United States ; P01AG003991/NH/NIH HHS/United States ; ARUK-PPG2023B-023//Alzheimer Research UK/ ; },
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/drug therapy/therapy/metabolism ; *Neuroimaging/methods ; *Brain/diagnostic imaging/metabolism ; *Amyloid beta-Peptides/metabolism ; *Amyloid/metabolism ; },
abstract = {In 2011, a workgroup of the Alzheimer's Association Research Roundtable introduced recommendations for detecting and monitoring amyloid-related imaging abnormalities (ARIA) in Alzheimer's disease (AD) clinical trials. Since then, anti-amyloid immunotherapies have received regulatory approval for AD treatment and are beginning to enter clinical practice, underscoring the importance of informing healthcare providers, researchers, and patients about ARIA's implications in real-world settings. In response, the Alzheimer's Association convened a new workgroup to review current knowledge of ARIA, including underlying mechanisms, clinical presentations, associated risk factors, mitigation strategies, radiologic detection methods, patients' perspectives in treatment decision-making, and outstanding challenges. Here, we outline key insights from this workgroup, highlighting that effective ARIA detection and monitoring in clinical practice requires adherence to robust protocols to mitigate risks and enhance patient safety. Limited availability of clinical and pathologic data on predictors of symptomatic and severe ARIA underscores the importance of continued real-world data collection.},
}

Humans
*Alzheimer Disease/diagnostic imaging/drug therapy/therapy/metabolism
*Neuroimaging/methods
*Brain/diagnostic imaging/metabolism
*Amyloid beta-Peptides/metabolism
*Amyloid/metabolism

@article {pmid42015793,
year = {2026},
author = {Gao, L and Watson, R and Yassi, N},
title = {Cost-Effectiveness of Donanemab for Early Alzheimer Disease in Australia.},
journal = {The Medical journal of Australia},
volume = {224},
number = {4},
pages = {e70186},
doi = {10.5694/mja2.70186},
pmid = {42015793},
issn = {1326-5377},
mesh = {Humans ; *Alzheimer Disease/drug therapy/economics ; Cost-Benefit Analysis ; Australia ; Quality-Adjusted Life Years ; Aged ; Markov Chains ; *Antibodies, Monoclonal, Humanized/economics/therapeutic use ; Male ; Disease Progression ; Female ; Amyloid beta-Peptides ; },
abstract = {OBJECTIVES: To evaluate the cost-effectiveness of donanemab, an anti-amyloid-β monoclonal antibody recently approved in Australia, for treating early-stage Alzheimer disease with confirmed amyloid-β pathology from healthcare system and societal perspectives.

DESIGN: A Markov microsimulation model simulating long-term Alzheimer disease progression, treatment costs and health outcomes for donanemab compared with standard care.

SETTING, PARTICIPANTS: Australian healthcare context, applying published clinical and economic inputs. A hypothetical cohort of people with early symptomatic Alzheimer disease, consistent with TRAILBLAZER-ALZ eligibility criteria: mean age 75 years, amyloid-β-positive, with mild cognitive impairment or mild dementia because of Alzheimer disease and excluding individuals with APOEE4 homozygotes, in line with the Australian labelling. Donanemab administered every 4 weeks with magnetic resonance imaging (MRI)-based amyloid-β-related imaging abnormalities monitoring and treatment suspension upon amyloid-β clearance or progression to severe Alzheimer disease, compared with standard care.

MAIN OUTCOME MEASURES: Incremental costs, quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs). Secondary analyses included sensitivity and distributional equity analyses.

RESULTS: Donanemab increased total healthcare costs ($300,689 vs. $178,121) and societal costs ($389,113 vs. $283,618) compared with standard care per capita, while improving health outcomes (4.38 vs. 4.01 QALYs) per capita. The ICER was $342,424 per QALY from the healthcare perspective and $294,701 per QALY from the societal perspective, exceeding frequently cited Australian willingness-to-pay thresholds. Sensitivity analyses identified drug cost and efficacy as key drivers of uncertainty. Distributional analysis suggested inequitable health gains by remoteness because of differences in diagnostic and treatment infrastructure.

CONCLUSION: Donanemab provides clinical benefits but is unlikely to be cost-effective under current Australian thresholds. Policymakers should balance economic evidence with unmet need, equity considerations and healthcare sustainability when making reimbursement decisions. Further research using real-world evidence and disaggregated analyses by geography and socioeconomic status is warranted.},
}

Humans
*Alzheimer Disease/drug therapy/economics
Cost-Benefit Analysis
Australia
Quality-Adjusted Life Years
Aged
Markov Chains
*Antibodies, Monoclonal, Humanized/economics/therapeutic use
Male
Disease Progression
Female
Amyloid beta-Peptides

@article {pmid42015806,
year = {2026},
author = {Zhang, X and Elmansy, R},
title = {Exploring Influencing Factors of Medication Adherence Among Chinese Patients With Alzheimer Disease: Delphi Study Informing Future Artificial Intelligence-Supported Interventions.},
journal = {JMIR formative research},
volume = {10},
number = {},
pages = {e89508},
doi = {10.2196/89508},
pmid = {42015806},
issn = {2561-326X},
mesh = {Humans ; *Alzheimer Disease/drug therapy/psychology ; Delphi Technique ; *Artificial Intelligence ; Male ; Female ; China ; *Medication Adherence/psychology ; Aged ; Middle Aged ; East Asian People ; },
abstract = {BACKGROUND: Alzheimer disease (AD) affects cognition, treatment adherence, family connections, and health care resource allocation. Most patients with AD have low adherence to medication therapy due to the limitations associated with cognitive impairment. Therefore, increasing the involvement of patients and their family members in medication management is important to improve treatment outcomes and reduce the burden of care.

OBJECTIVE: This study explores the potential application of artificial intelligence (AI) in medication management for Chinese patients with early- to mid-stage AD focusing on enhancing medication adherence. The study first predicts and evaluates key factors through an online Delphi study, which provides a basis for their subsequent incorporation into the AI model as input variables to enable prediction of medication-taking behaviors. Since AI research in medication management for this population is still undeveloped, this paper further explores the multiple potentials of AI from a theoretical view, including drug dosage optimization, multidrug interaction detection, and family education support. It will provide a preliminary direction and theoretical basis for the development of an intelligent medication management system in the future.

METHODS: The exploratory online Delphi study with no modification predicted the key factors influencing medication adherence. Based on the results, the study confirmed the potential of AI to improve adherence. Participation by 12 experts in 3 rounds systematically assessed the core elements influencing patients' adherence to their medication.

RESULTS: Family care, social support, environmental factors, emotional support, and patient behaviors were identified as the primary factors influencing medication adherence among Chinese patients with AD. These factors were validated and ranked through iterative Delphi rounds, with family care and social support receiving the highest importance scores. The Wilcoxon signed-rank test indicated no significant difference between rounds (P=.06), supporting the stability of the consensus. These findings establish a foundational set of variables for AI systems that predict and enhance medication adherence.

CONCLUSIONS: This study highlights the critical factors affecting medication adherence by Chinese patients with AD. It was designed as an exploratory online Delphi study to identify and prioritize key influencing factors, rather than to validate a specific AI-based system, and the findings provide a theoretical foundation for future AI-informed interventions. The results also indicate theoretical potential roles for AI in supporting medication management, such as optimizing drug dosage, detecting multidrug interactions, and enhancing family education.},
}

Humans
*Alzheimer Disease/drug therapy/psychology
Delphi Technique
*Artificial Intelligence
Male
Female
China
*Medication Adherence/psychology
Aged
Middle Aged
East Asian People

@article {pmid42016208,
year = {2026},
author = {Shah, KB and Xiang, L and Shah, SK and Adler, RR and Weissman, JS},
title = {Dementia Is Associated With Higher One-Year Mortality and Worse Patient-Centered Outcomes in Patients Undergoing Percutaneous Coronary Intervention for Acute Myocardial Infarction and Cardiogenic Shock.},
journal = {Cardiology research},
volume = {17},
number = {2},
pages = {128-135},
pmid = {42016208},
issn = {1923-2829},
abstract = {BACKGROUND: Recent trial data demonstrates improved outcomes for the treatment of ST-segment elevation myocardial infarction (STEMI) and cardiogenic shock (CS) with percutaneous coronary intervention (PCI) supported by mechanical circulatory support (MCS). Clinical outcomes in patients with Alzheimer's disease and related dementias (ADRD), however, remain unknown, as these patients were excluded from relevant trials. Physicians and caregivers struggle to navigate time-sensitive decision making for patients with ADRD presenting with STEMI or CS. The aims of this study were to assess the association of ADRD with outcomes of PCI with MCS in the setting of STEMI or CS.

METHODS: We compared outcomes among Medicare fee-for-service (FFS) beneficiaries aged 66 years or older, with and without ADRD, who underwent PCI with MCS for STEMI or CS from July 1, 2017 to December 31, 2019. The primary clinical outcome was inpatient mortality, and secondary clinical outcomes were 1-year mortality, complications, and readmissions. Patient-centered outcomes were time-at-home ratio and discharge to a higher level of care.

RESULTS: A total of 13,110 patients undergoing PCI with MCS for STEMI or CS met study criteria, and 988 (7.5%) patients carried a diagnosis of ADRD. Patients with ADRD were more likely to be older (81.1 vs. 75.5, P < 0.001) and frail (47.0% vs. 22.0%, P < 0.001). Inpatient mortality was similar between groups (odds ratio (OR), 1.05; 95% confidence interval (CI), 0.92-1.21), but 1-year mortality was higher among patients with ADRD (OR, 1.41; 95% CI, 1.21-1.64). Major complications and readmissions were similar between groups. Patients with ADRD were more likely to be discharged to a higher level of care (OR, 1.46; 95% CI, 1.16-1.82) than those without ADRD but demonstrated a similar time-at-home ratio.

CONCLUSIONS: Patients with ADRD demonstrate similar rates of inpatient mortality and major complications but have higher rates of 1-year mortality and discharge to higher levels of care.},
}

@article {pmid42016241,
year = {2026},
author = {Sun, M and He, J and Song, H and Ma, Z and Zhang, X and Li, J and Yao, Y},
title = {Structural Characterization and Anti-Alzheimer's Disease Effect of Polysaccharides From Stellariae Radix.},
journal = {Food science & nutrition},
volume = {14},
number = {3},
pages = {e71604},
pmid = {42016241},
issn = {2048-7177},
abstract = {Stellariae Radix, a frequently employed traditional Chinese medicine, originates from the dried roots of Stellaria dichotoma L. var. lanceolata Bge. To elucidate the structural characteristics and anti-Alzheimer's disease (AD) efficacy of S. dichotoma polysaccharides (SDP), SDP was extracted and comprehensively characterized using ultraviolet-visible spectroscopy (UV-Vis), Fourier-transform infrared spectroscopy (FT-IR), nuclear magnetic resonance (NMR) spectroscopy and high-performance liquid chromatography (HPLC). The results revealed that SDP is composed of galactose, glucose, arabinose, galacturonic acid, mannose, and rhamnose at a molar ratio of 5.561:2.224:0.802:0.616:0.613:0.184. In vitro experiments demonstrated that SDP exhibited potent scavenging activities against ABTS, DPPH, and hydroxyl radicals in a dose-dependent manner, with the average scavenging rates reaching 99.07%, 89.44% and 56.43% respectively at the concentration of 5 mg/mL. In a C57BL/6J mouse model of AD, administration of SDP (50-200 mg/kg) significantly ameliorated cognitive dysfunction, increased the hippocampal levels of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), decreased the malondialdehyde (MDA) content, and regulated the expression of oxidative stress-related proteins, including Nrf2, Keap1 and NQO1. These findings indicate that SDP possesses antioxidant and neuroprotective properties, suggesting its potential therapeutic value for the treatment of AD.},
}

@article {pmid42016382,
year = {2026},
author = {Yi, S and Zou, J and He, X and Chen, H and Lin, Z and Zhang, L and Zhu, Y and Zuo, Z and Chen, Z and Hu, X and Niu, L},
title = {Transcranial Ultrasound Stimulation Pulsed at 40 Hz Improves Cognition and Neuroinflammation in Female Mice with Alzheimer's Disease.},
journal = {Research (Washington, D.C.)},
volume = {9},
number = {},
pages = {1244},
pmid = {42016382},
issn = {2639-5274},
abstract = {Recent advances in transcranial ultrasound stimulation (TUS) pulsed at 40 Hz have demonstrated the potential to ameliorate cognitive deficits in mouse models of Alzheimer's disease. However, technical barriers remain as general anesthesia is required for mice, which restricts the accurate elucidation of biological mechanisms and behavioral effects under awake physiological conditions. Here, we report a wearable, free-moving ultrasound stimulation system that delivers TUS pulsed at 40 Hz to female 5xFAD transgenic mice to systematically evaluate the behavioral outcomes and underlying mechanistic pathways. Among the treatment groups, a 14-d regimen at an acoustic intensity of 2.14 W/cm[2] yielded the optimal cognitive outcome in Alzheimer's disease mice, which was consistently verified across Y-maze and Morris water maze tests. Additionally, this group showed reduced Aβ plaque deposition and increased plaque-associated microglial activity. Furthermore, enhanced gamma oscillations in the hippocampus were detected following treatment. RNA sequencing revealed modulation of innate immune and inflammatory pathways. Corresponding molecular analysis demonstrated a marked down-regulation in RIPK1, phosphorylated NF-κB, and necroptosis markers, alongside reductions in key pro-inflammatory cytokines (IL-6, IL-1β, and TNF-α). Collectively, our findings suggest that the cognitive improvement observed after treatment with TUS pulsed at 40 Hz may be linked to the modulation of neuroinflammatory and necroptotic pathways, possibly involving RIPK1/NF-κB signaling.},
}

@article {pmid42018938,
year = {2026},
author = {Haghighi, FH and Xie, J and Ebert, ET and Siahaan, TJ},
title = {Progress and challenges in drug delivery for the treatment of Alzheimer's disease.},
journal = {Expert opinion on drug delivery},
volume = {},
number = {},
pages = {},
doi = {10.1080/17425247.2026.2663114},
pmid = {42018938},
issn = {1744-7593},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a neurodegenerative disorder marked by declining memory and cognitive function. Despite recent advances to slowdown early-stage progression, no curative therapies exist due to challenges in delivering neuroregenerative agents to the brain.

AREAS COVERED: This review examines recent research on strategies to modulate the blood-brain barrier (BBB) to enhance delivery of small-to-large molecules through the paracellular pathway into the brain for potential treatments of AD. A literature search was conducted using PubMed and Scopus covering studies published between 2016 and 2026.

EXPERT OPINION: BBB modulation technologies are advancing rapidly and offer real potential to improve delivery of therapeutics in AD patients. Hyperosmotic method has been successfully used to deliver anticancer drugs to treat brain tumor patients and can be used for AD. Recently, focused ultrasound (FUS) has been used to disrupt the BBB at a targeted brain region to enhance paracellular permeation of drug molecules to the brain. Finally, drug permeation through the BBB paracellular pathway can also be enhanced by modulating the protein-protein interactions in the intercellular junctions using BBB modulators (BBBMs). This review covers the mechanisms, advantages, and limitations of these methods as well as recent studies to enhance therapeutic agents for AD and other brain diseases.},
}

@article {pmid42019114,
year = {2026},
author = {Liu, Y and Jiang, Z and Chen, D and He, Z and Ning, W and Wang, S and Guan, L},
title = {Design, synthesis, and biological evaluation of Chromene-Phenylpiperazine-Chalcone hybrids as multi-target-directed ligands for the treatment of Alzheimer's disease.},
journal = {Bioorganic & medicinal chemistry},
volume = {138},
number = {},
pages = {118670},
doi = {10.1016/j.bmc.2026.118670},
pmid = {42019114},
issn = {1464-3391},
abstract = {A novel series of chromene-phenylpiperazine-chalcone hybrids was rationally designed, synthesized and evaluated as multi-target-directed ligands (MTDLs) for Alzheimer's disease (AD). Among them, compound 9 s exhibited selective equine serum butyrylcholinesterase (eqBuChE, IC50 = 0.13 μM) and concurrent monoamine oxidase B (MAO-B, IC50 = 1.63 μM) inhibitory activities. Kinetic and molecular docking studies indicated that 9 s acts as a mixed-type dual-site inhibitor. In silico modeling suggests that the binding pose is stabilized by a predicted pseudo-seven-membered ring. Furthermore, 9 s facilitated the disassembly of self-aggregated and Cu[2+]-induced Aβ1-42 fibrils. In BV-2 microglial cells, it demonstrated a high safety margin (> 380-fold effective concentration), accelerated intracellular Aβ clearance, and subsequently attenuated LPS-induced NO production. In vivo evaluations revealed low acute toxicity (LD50 > 1000 mg/kg). Oral administration of 9 s successfully reversed scopolamine-induced spatial working memory deficits in mice. These findings validate the drug-like 9 s as an orally efficacious MTDL candidate that provides symptomatic cognitive relief, while possessing promising in vitro disease-modifying potential for AD therapy.},
}

@article {pmid42019137,
year = {2026},
author = {Otani, K and Ishihara, H and Nakamura, T and Kawabe, K},
title = {Implementation and service impact of anti-amyloid therapy in a psychiatry-led dementia care program: Real-world evidence from a Japanese regional dementia center.},
journal = {General hospital psychiatry},
volume = {100},
number = {},
pages = {208-214},
doi = {10.1016/j.genhosppsych.2026.04.006},
pmid = {42019137},
issn = {1873-7714},
abstract = {BACKGROUND: Amyloid-targeting antibody therapies for Alzheimer's disease require substantial diagnostic infrastructure including amyloid PET imaging, repeated MRI monitoring, and specialized clinical evaluation. In Japan, psychiatrists frequently lead dementia diagnosis and treatment in general hospitals through designated Regional Dementia Medical Centers; however, the real-world service impact of implementing these therapies in psychiatry-led dementia care remains poorly described.

METHODS: We conducted a retrospective analysis of administrative and billing data from a Regional Dementia Medical Center at Kakogawa Central City Hospital, Japan. Data included amyloid PET imaging, anti-amyloid monoclonal antibody therapy (lecanemab and donanemab), and associated reimbursement and acquisition costs between May 2024 and January 2026. This study was conducted as part of institutional quality improvement activities.

RESULTS: During the observation period, 72 amyloid PET examinations were performed. Results were amyloid-positive in 50 cases (69%) and negative in 22 cases (31%). Of 50 amyloid-positive patients, 38 (76%) initiated anti-amyloid therapy (lecanemab: 14; donanemab: 24), with 389 total treatment administrations. ARIA was detected in 8 treated patients (21%), all asymptomatic. MRI examinations for ARIA monitoring increased from 5 in FY2023 to 58 in FY2024 and 139 in FY2025. Total reimbursement amounted to 35.4 million yen for lecanemab and 25.7 million yen for donanemab. Drug acquisition costs represented approximately 97% of reimbursement, with margins averaging 3%. Outpatient revenue per visit increased 141% from 5560 yen in FY2022 to 13,401 yen in FY2025, despite stable visit volumes (FY2022: 11,203; FY2024: 10,223).

CONCLUSIONS: Implementation of amyloid-targeting antibody therapy in psychiatry-led dementia care substantially increases service activity and hospital revenue streams but generates narrow financial margins due to high drug acquisition costs. All ARIA cases were asymptomatic, supporting the feasibility of systematic monitoring within a psychiatry-led model in this setting. These findings highlight important structural and economic considerations for the sustainability of these programs in general hospital psychiatry.},
}

@article {pmid42019901,
year = {2026},
author = {Tseng, CH},
title = {The hidden link between diabetes and dementia: Findings from recent epidemiological studies.},
journal = {Biomedical journal},
volume = {},
number = {},
pages = {100985},
doi = {10.1016/j.bj.2026.100985},
pmid = {42019901},
issn = {2320-2890},
abstract = {Recent epidemiological studies investigating the link between diabetes mellitus and dementia or Alzheimer's disease are narratively reviewed. Diabetes mellitus is associated with a significantly higher risk of dementia by 56%, more predominant for vascular dementia than Alzheimer's disease and tau pathology is more remarkable than amyloid β deposition. The increased risk is related to the burden of microvascular and macrovascular diseases in a dose-response pattern; and a threshold effect between glycemic control and dementia risk is observed. A treatment target of hemoglobin A1c < 7% may be optimal for reducing the risk of dementia but hypoglycemia should be avoided. Antidiabetic drugs such as metformin, pioglitazone, sodium-glucose co-transporter 2 inhibitors and glucagon-like peptide 1 receptor agonists may show beneficial effects on dementia in observational studies. In a Taiwanese cohort study acarbose is also associated with a lower risk of dementia in female diabetes patients. When considering the repurposing of antidiabetic drugs in the treatment of patients with Alzheimer's disease, low-dose insulin detemir shows a promising effect in a network meta-analysis. A phase 3 clinical trial (MET-FINGER) is being conducted to investigate whether metformin plus lifestyle intervention can be effective in the prevention of Alzheimer's disease. Hyperuricemia, though considered a potential component of metabolic syndrome, seems to be associated with a lower risk of dementia. Sex hormones play some roles in cognitive function and females present a higher risk of dementia than males. However, additional studies are required to explore the impacts of sex and sex hormones on the development of dementia and Alzheimer's disease.},
}

@article {pmid42020091,
year = {2026},
author = {Mewton, L and Winter, V and Hoy, N and Visontay, R and Davies, S and Kochan, N and Baillie, A and Chapman, C and Newton, NC and Sunderland, M and Sachdev, PS and Teesson, M},
title = {Effect of the online Rethink My Drink alcohol intervention on alcohol use and cognition in older adults in Australia: a randomised controlled trial.},
journal = {The Lancet. Public health},
volume = {11},
number = {5},
pages = {e318-e328},
doi = {10.1016/S2468-2667(26)00056-3},
pmid = {42020091},
issn = {2468-2667},
mesh = {Humans ; Aged ; Male ; Female ; Middle Aged ; Australia/epidemiology ; *Alcohol Drinking/prevention & control/epidemiology ; *Cognitive Dysfunction/prevention & control ; *Cognition ; *Internet-Based Intervention ; },
abstract = {BACKGROUND: Alcohol use is increasing among older adults and is associated with cognitive impairment and dementia. The efficacy of scalable approaches to reduce alcohol use and related harms in older adults has not been tested. This study aimed to evaluate the efficacy of an online alcohol intervention in reducing alcohol use and cognitive decline in older adults.

METHODS: We did a two-arm, parallel-group, randomised controlled trial online among community-based older adults (aged 60-75 years) who screened as having high-risk alcohol use (scoring ≥5 on the Alcohol Use Disorder Identification Test). Exclusion criteria included diagnosis of a neurological disorder (eg, dementia, Parkinson's disease, or multiple sclerosis), previous prescription of medication for the treatment of Alzheimer's disease, and non-correctable visual impairment. Participants across Australia were randomly assigned (1:1) to the Rethink My Drink programme (a four-module online intervention designed specifically for older adults) or an active control group (online information booklet), stratified by age and gender. Participants and the lead statistician were masked to group assignment. Number of drinks in the past month and global cognition Z scores assessed via the Cambridge Neuropsychological Test Automated Battery were the primary outcomes, assessed at the 12-month follow-up. Intention-to-treat analyses were conducted using generalised mixed effects regression. The trial was registered with the Australian New Zealand Clinical Trials Registry (ACTRN12621000292875; March 16, 2021), and is completed.

FINDINGS: Between Oct 29, 2021, and June 6, 2022, 3766 participants were screened for eligibility, 2878 were excluded (1390 did not meet inclusion criteria, 1047 declined to participate, and 441 had incomplete baseline assessments), and 888 completed baseline assessments and were randomly assigned. 448 participants were assigned to the Rethink My Drink intervention and 440 were assigned to receive the online patient information booklet. Data from 445 participants in the intervention group and 438 participants in the control group were analysed. Most participants (872 [99%] of 883) identified as White, 685 (78%) participants were female and 198 (22%) were male, and the mean age was 65·3 years (SD 3·9). At 12 months, those in the intervention group had greater reductions in their monthly number of standard drinks when compared with the control group (difference, 5·02 standard drinks [95% CI 1·81 to 8·24]; p<0·0001). For global cognition, the difference between the two groups was not significant at 12 months (difference 0·12 SDs [95% CI -0·05 to 0·29]; p=0·16). Two participants (one in the control group and one in the intervention group) spontaneously reported non-serious adverse events that were assessed as unrelated to the trial.

INTERPRETATION: Rethink My Drink is an effective and scalable intervention that has considerable potential for reducing alcohol use among older adults.

FUNDING: Dementia Centre for Research Collaboration.},
}

Humans
Aged
Male
Female
Middle Aged
Australia/epidemiology
*Alcohol Drinking/prevention & control/epidemiology
*Cognitive Dysfunction/prevention & control
*Cognition
*Internet-Based Intervention

@article {pmid42006351,
year = {2026},
author = {Abskharon, R and Jiang, YX and Sawaya, MR and Ge, P and Zhang, J and Boyer, DR and Dolinsky, JL and Pi, J and Cascio, D and Guo, F and Eisenberg, DS},
title = {Structural evidence that RNA contributes to polymorphism of tau amyloid fibrils.},
journal = {iScience},
volume = {29},
number = {4},
pages = {115501},
pmid = {42006351},
issn = {2589-0042},
abstract = {RNA colocalizes with tau deposits in Alzheimer's disease (AD) and drives tau aggregation in vitro. Previously, we determined a cryogenic-electron microscopy (cryo-EM) structure of fibrils of full-length tau bound to unfractionated mammalian RNA, revealing a small tau C-terminal core. Here, we present the cryo-EM structure of fibrils of full-length recombinant tau bound to unfractionated mammalian RNA seeded by AD-extracted tau fibrils. This structure reveals an expanded tau C-terminal core resembling AD tau fibrils. RNA sequencing identified 18S ribosomal RNA as the primary fibril-bound species. Next, we determined the cryo-EM structure of fibrils of full-length recombinant tau bound to mammalian 18S ribosomal RNA, revealing a core that consists of the R2 to R4 repeat domains previously seen in pathological tau fibrils. All our recombinant RNA-tau fibrils dissolve upon RNase treatment. Tau fibrils adopt distinct folds in the presence of different RNAs, suggesting RNA is a cofactor capable of shaping tau fibril polymorphism.},
}

@article {pmid42006409,
year = {2026},
author = {Davidson, MH and Hsieh, A and de Kleer, M and Szarek, MS and Scheltens, P and Vijverberg, E and Johnson, A and Ditmarsch, M and Kastelein, JJP},
title = {The emerging role of CETP inhibition in the prevention of Alzheimer's disease.},
journal = {American journal of preventive cardiology},
volume = {26},
number = {},
pages = {101442},
pmid = {42006409},
issn = {2666-6677},
abstract = {We recently showed that patients with atherosclerotic cardiovascular disease (ASCVD) carry a substantial but largely unrecognized burden of early Alzheimer's disease (AD) pathology. In the BROADWAY pivotal phase 3 lipid-lowering trial, nearly half of participants with high-risk ASCVD had plasma p-tau217 concentrations above thresholds associated with preclinical AD, yet none had undergone evaluation for cognitive impairment. In this population, apolipoprotein E ε4 (APOE4) carriers were disproportionately represented among those with the highest p-tau217 levels. These findings expose a critical gap between cardiovascular care and dementia prevention and raise the question whether interventions targeting shared pathophysiology could address both conditions simultaneously. Cholesteryl ester transfer protein (CETP) inhibition has emerged as a candidate for this dual role. In BROADWAY, obicetrapib reduced p-tau217 progression across the study population, with effects most pronounced in APOE4 carriers. In fact, treatment differences favoring obicetrapib were observed across all measured AD biomarkers in high-risk subgroups, including neurofilament light chain, glial fibrillary acidic protein, and the amyloid-beta (Aβ) 42:40 ratio. Unlike approaches that target downstream pathology, such as amyloid plaques already deposited in the brain or the inflammatory consequences of established disease, CETP inhibition may address the upstream processes involved in initiating the pathological cascade: lipid dysregulation, cholesterol ester accumulation in glial cells, impaired cholesterol efflux, lipid peroxidation, oxysterol formation, and deficient antioxidant transport. This review examines the biological rationale linking APOE4 status to disordered lipid metabolism in both peripheral and central compartments, the genetic and epidemiological evidence supporting CETP as a therapeutic target, the mechanisms through which CETP inhibition might confer neuroprotection, and the clinical data suggesting obicetrapib as the first oral agent associated with favorable changes in AD biomarkers across both amyloid and tau axes in individuals at high genetic risk for the development of AD.},
}

@article {pmid42006781,
year = {2026},
author = {Raikes, AC and Garza, M and Murrell, AN and Brinton, RD},
title = {Meta analysis of glucose metabolism across Alzheimer's, Parkinson's and ALS Reveals emergence of adaptive brain glucometabolic responses and associated neurological functional profiles.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.07.26350339},
pmid = {42006781},
abstract = {IMPORTANCE: Glucose metabolic dysregulation in brain is a common feature of late-onset age-associated neurodegenerative disease (A [2] ND). Prior meta-analyses have identified disease-specific effects compared to healthy, unimpaired individuals. Yet, a unifying A [2] ND glucose dysregulation spatial signature remains undescribed.

OBJECTIVE: To determine the common signature of dysregulated glucose metabolism on FDG-PET using activation likelihood estimation (ALE) meta-analyses across A [2] ND.

DATA SOURCES: Searches were conducted using MEDLINE, Embase, PsycINFO, Scopus, and Cochrane from inception through July 2025. The search terms included controlled vocabulary and keywords for four neurodegenerative diseases Parkinson Disease, Amyotrophic Lateral Sclerosis, Alzheimer Disease, and Multiple Sclerosis, Fluorodeoxyglucose F18, glucose, and positron-emission tomography (PET).

STUDY SELECTION: Studies comparing adults with late-onset neurodegenerative diseases to non-diseased controls using FDG-PET to quantify brain glucose uptake and reporting whole-brain coordinate findings in either Talairach or Montreal Neurological Institute space were included.

DATA EXTRACTION AND SYNTHESIS: Three researchers, assisted by an AI screening tool, screened 7275 potential titles and abstracts for inclusion. Full texts were then retrieved for potentially relevant articles and were evaluated by three researchers using prespecified inclusion/exclusion criteria.

MAIN OUTCOMES AND MEASURES: Cluster peak and subpeak coordinates, cluster-wise t-or Z-values, and annotations indicating the disease of interest, whether the outcome was for hyper-(disease group > control) or hypometabolism (disease group < control), were extracted from included texts and analyzed using ALE.

RESULTS: A total of 130 FDG-PET studies were included in the meta-analysis, with a combined sample of 5298 individuals with A [2] ND and 3499 controls. Meta-analyses revealed dysregulated glucose metabolism as a unifying feature across A [2] ND which included both hypo-and hypermetabolic patterns. Neuroanatomical metabolic pattern was unique and disease specific. Each A [2] ND metabolic phenotype was associated with unique and complex patterns of neurological functionalities.

CONCLUSIONS AND RELEVANCE: These data demonstrate dysregulated glucose metabolism as a common A [2] ND feature, suggesting responsive remodeling of neural bioenergetics. While hypometabolism is a common research focus, due to functional relevance, hypermetabolism may reflect a compensatory, maladaptive, or neuroinflammatory signal, that requires focused investigation. A [2] ND prevention and treatment efficacy may depend on addressing bidirectional metabolic dysregulation in addition to disease-specific drivers of pathology.},
}

@article {pmid42008282,
year = {2026},
author = {Burns, JM and Woodward, JL and Morris, JK and Townley, RA},
title = {Reimagining Care Delivery for Alzheimer Disease.},
journal = {JAMA neurology},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamaneurol.2026.0801},
pmid = {42008282},
issn = {2168-6157},
}

@article {pmid42008483,
year = {2026},
author = {Zhang, X and Wang, Z and Sun, M and Bao, Q and Chen, Z and Liu, Y and Wang, Z and Ye, F and Yang, Z and Du, X and Zhang, H and Mou, X and He, X and Li, D and Wu, K and Yao, J and Zhong, W and Xu, P and Yang, S and Zhao, L and Yin, Z and Liang, F},
title = {Acupuncture for amnestic mild cognitive impairment: Study protocol for a multicenter, single-blinded, long-term, randomized controlled trial.},
journal = {PloS one},
volume = {21},
number = {4},
pages = {e0346717},
doi = {10.1371/journal.pone.0346717},
pmid = {42008483},
issn = {1932-6203},
mesh = {Humans ; *Cognitive Dysfunction/therapy ; *Acupuncture Therapy/methods ; Single-Blind Method ; Aged ; Female ; Male ; Treatment Outcome ; *Amnesia/therapy ; Multicenter Studies as Topic ; Randomized Controlled Trials as Topic ; Middle Aged ; Aged, 80 and over ; },
abstract = {BACKGROUND: Amnestic mild cognitive impairment (aMCI), a common neurodegenerative disease affecting older adults, has garnered significant research interest over the past few years. While previous studies have suggested that acupuncture holds promise as a clinical intervention to improve cognitive function in patients with aMCI, the long-term effect of acupuncture treatment for aMCI remains unclear.

METHODS: This is a multicenter, single-blinded, randomized controlled trial (RCT) with a long-term follow-up.166 patients diagnosed with aMCI will be randomly divided into acupuncture group (AG) and sham acupuncture group (SA). The intervention will last for 12 weeks (2 sessions per week), follow-up for 48 weeks, and the study will last a total of 60 weeks. The primary outcomes are the changes in the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog) score from baseline to week 12 and from baseline to week 60. Generalized estimating equations (GEE) will be used to assess the impact of the acupuncture intervention on outcome variables over time at baseline and weeks 12, 24, 48, and 60.

DISCUSSION: This protocol outlines a detailed procedure for a multicenter RCT designed to further evaluate the long-term effect of acupuncture in managing aMCI. We anticipate that the findings of this research will provide valuable insights and evidence-based recommendations for the clinical management of this patient population.

TRIAL REGISTRATION: The trial was registered at Chinese Clinical Trial Registry on 28 May 2024 (Number: ChiCTR2400084932).},
}

Humans
*Cognitive Dysfunction/therapy
*Acupuncture Therapy/methods
Single-Blind Method
Aged
Female
Male
Treatment Outcome
*Amnesia/therapy
Multicenter Studies as Topic
Randomized Controlled Trials as Topic
Middle Aged
Aged, 80 and over

@article {pmid42008564,
year = {2026},
author = {Al-Anbari, E and Karshenas, H and Shoushtarian, B},
title = {Normalizing flow based neural processes for Alzheimer's disease progression prediction.},
journal = {PloS one},
volume = {21},
number = {4},
pages = {e0345958},
doi = {10.1371/journal.pone.0345958},
pmid = {42008564},
issn = {1932-6203},
mesh = {Humans ; *Alzheimer Disease/diagnosis/diagnostic imaging/physiopathology/pathology/genetics ; Disease Progression ; Cognitive Dysfunction/diagnosis ; Aged ; Male ; Female ; Neuroimaging ; },
abstract = {As one of the most common neurodegenerative diseases, Alzheimer's accounts for serious health problems worldwide. Accurate detection and prediction of this disease contribute to the health system for better prevention and interventions in the treatment plans. However, traditional models designed for prediction and classification face several challenges, including handling complex data, which neglects many data points for the diagnosis. To overcome this challenge, we propose a novel model based on the integration of Neural Processes (NPs) and Normalizing Flows (NFs). The dataset used for this study is the Alzheimer's Disease Prediction of Longitudinal Evolution (TADPOLE). We selected various features to build an efficient model, including cognitive, neuroimaging, genetic, and demographic data. which contains three classes: Cognitively Normal (CN), Mild Cognitive Impairment (MCI), and AD. The proposed model is able to capture the temporal dependencies present in the complex distribution. The stochastic processes were modeled by NPs, while NF was able to transform the Gaussian distributions from simple to complex distributions, allowing them to model a wide range of data distributions. The prediction performance and robustness have been enhanced since this framework is able the adapt to every patient trajectory and generalizing across different populations. The model was compared with other models, such as SNP, deep geometric learning, Manifold DCNN, and other models. Our model (SNP-NF) made an improvement regarding mAUC, Precision, and Recall, approximately 3%,1%, and 0.7%, respectively from our previous model, which utilized only NP. These results demonstrate the capability of the proposed approach to provide early detection and personal treatment plans for patients suffering from this disease.},
}

Humans
*Alzheimer Disease/diagnosis/diagnostic imaging/physiopathology/pathology/genetics
Disease Progression
Cognitive Dysfunction/diagnosis
Aged
Male
Female
Neuroimaging

@article {pmid42009326,
year = {2026},
author = {Garg, A and Shaw, R},
title = {SSiamese Capsule Network (SNNCap) : Cognitive Analysis for Alzheimer's Disease Classification from MRI Data.},
journal = {IEEE transactions on image processing : a publication of the IEEE Signal Processing Society},
volume = {PP},
number = {},
pages = {},
doi = {10.1109/TIP.2026.3683547},
pmid = {42009326},
issn = {1941-0042},
abstract = {Alzheimer's Disease (AD) detection is essential for timely treatment and better patient care. Magnetic Resonance Imaging (MRI) is a technique in which radio waves and magnetic fields are used to capture high-resolution, multi-dimensional representations of brain structures. This high-resolution imaging capability makes MRI a key tool for diagnosing neurological disorders such as Alzheimer's disease. However, the problem is to correctly classify the fresh MRI scans of patients. Researchers have proposed a deep learning-based method for Alzheimer's disease diagnosis using a Siamese Convolutional Neural Network (SCNN) with three ResNet-34 branches trained on structural MRI data. However, this method relies solely on ResNet34 for feature extraction which struggles to preserve spatial relationship due to pooling operations, causing loss of positional information. Other researchers have explored methods like attention mechanisms and 3D convolutional networks to capture spatial dependencies. However, these methods underperform by missing brain complexity or needing high resources without consistent accuracy. In this study, we propose a cognitively inspired approach for classifying MRI images as Non Demented, Very Mild Demented, Mild Demented and Moderate Demented using Siamese Capsule Network (SNNCap). SNNCap uses ResNet-18 for feature extraction and capsule layers to preserve spatial and part-whole relationships in the images. It compares a test image against a few known reference examples per class. This reference-based validation closely mimics cognitive reasoning, improving the system's generaliz-ability. The model achieves strong results on unseen data and demonstrates its effectiveness through classification reports and confusion matrices.},
}

@article {pmid42009978,
year = {2026},
author = {Wang, L and Venkatesh, S and Morris, M and Li, M and Srivastava, R and Visweswaran, S and Lopez, OL and Xia, Z and Cai, T},
title = {Stratification of Alzheimer's disease patients using knowledge-guided unsupervised latent factor clustering with electronic health record data.},
journal = {Communications medicine},
volume = {},
number = {},
pages = {},
doi = {10.1038/s43856-026-01511-y},
pmid = {42009978},
issn = {2730-664X},
abstract = {BACKGROUND: Prognostication for people with Alzheimer's disease (AD) at the point of care could improve clinical management.

METHODS: In this retrospective cohort study using the electronic health record (EHR) data from a large healthcare system (2011-2022), we applied an unsupervised latent factor clustering approach guided by knowledge graph embeddings to stratify AD patients into two groups at diagnosis (baseline) using clinical features in the two years preceding diagnosis. We prognosticated the risk of AD-related outcomes (nursing home admission and mortality) for the clusters in survival analyses adjusted for baseline confounders (age, gender, race, ethnicity, healthcare utilization, and comorbidities). To reflect real-world evolution in clinical trajectories, we updated patient stratification for patients remaining at risk one year post-diagnosis and repeated prognostication.

RESULTS: We stratify 16,411 AD patients into two groups at baseline (41% Group 1, 59% Group 2). Baseline Group 2 has a significantly lower risk of nursing home admission (HR [95% CI] = 0.804 [0.765, 0.844], p < .001) but comparable mortality risk to baseline Group 1 (HR [95% CI] = 1.008 [0.963, 1.056], p = 0.733). We re-stratify the 12,606 patients remaining at risk one year post-diagnosis (46% Group 1, 54% Group 2). Consistent with baseline, the updated Group 2 has a lower risk of nursing home admission (HR [95% CI] = 0.815 [0.766, 0.868], p < .001) but comparable mortality risk (HR [95% CI] = 0.977 [0.922, 1.035], p = .430) to Group 1.

CONCLUSIONS: Patient stratification enables outcome prognosis for AD patients. While baseline prognostication can guide early treatment and tailored management, dynamic prognostication may inform more timely interventions to improve long-term outcomes.},
}

@article {pmid42009995,
year = {2026},
author = {Tan, JY and Retinasamy, T and Lee, VLL and Radhakrishnan, AK and Yeong, KY},
title = {Exploring the role of tocotrienol-rich fraction (TRF) in ameliorating neuroinflammation.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {42009995},
issn = {1568-5608},
abstract = {Neuroinflammation is a chronic inflammatory response that contributes to synaptic dysfunction and neuronal damage, it is a common feature among various neurodegenerative diseases such as Alzheimer's Disease (AD), Parkinson's Disease (PD) and Huntington's Disease (HD). Tocotrienol-rich fraction (TRF) is a form of vitamin E that is known for its anti-inflammatory, antioxidant and neuroprotective properties. Yet, it has not been adequately investigated in both cellular and animal neuroinflammation models. In this study, the potential therapeutic effects of TRF were investigated in-vitro using BV2 microglial cells and also in-vivo in a pilot study using Sprague Dawley rats. TRF at 5 and 10 µg/mL were found to reduce nitric oxide (NO) and reactive oxygen species (ROS) levels. Furthermore, in-vivo treatment with TRF significantly increases the recognition index implying improvement in cognition ability. Gene expression analysis showed downregulation of RelA, TNF-α and IL-6 while NFE2L2 and BDNF were upregulated. These findings suggests that TRF may help mitigates neuroinflammation and oxidative stress, indicating its potential as a candidature for further investigation in neurodegenerative diseases associated with chronic neuroinflammation.},
}

@article {pmid42010230,
year = {2026},
author = {Liu, Y and Kunutsor, SK},
title = {Brain, benefit, or burden? Revisiting statins and cognitive function in older adults.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {42010230},
issn = {2509-2723},
abstract = {Statins are among the most widely prescribed medications for the prevention and treatment of cardiovascular disease, particularly in older adults. However, concerns regarding their potential adverse cognitive effects, including memory loss and dementia, have generated substantial debate and regulatory attention. This narrative review critically appraises current evidence on the relationship between statin use and cognitive outcomes in older adults, exploring both potential risks and benefits. We synthesized findings from randomized controlled trials (RCTs), observational cohort studies, meta-analyses, and Mendelian randomization studies. We also examined biological mechanisms, subgroup differences by statin type, and clinical considerations specific to older populations. Most RCTs have not demonstrated a harmful effect of statins on cognition, while observational studies have shown mixed results, including possible protective associations. Mechanistically, statins may exert both neuroprotective and neurotoxic effects, depending on their type, dose, and ability to cross the blood-brain barrier. Mendelian randomization analyses, including those involving over 100,000 individuals from the Danish general population, have largely found no causal effect of genetically proxied statin targets on dementia or neurodegenerative diseases. Importantly, older adults remain underrepresented in trials with cognitive outcomes, and real-world evidence is limited by confounding. Two large-scale randomized trials, PREVENTABLE and STAREE, are currently underway and poised to provide definitive evidence regarding the cognitive effects of statins in older populations. Current evidence does not support discontinuing statin therapy in older adults based solely on concerns about cognitive decline. Instead, decisions should be individualized, weighing cardiovascular benefit against cognitive risk, particularly in those with pre-existing cognitive impairment, polypharmacy, or frailty. Future research should prioritize cognition as a primary outcome in studies involving older populations.},
}

@article {pmid42011226,
year = {2026},
author = {Weiss, B and Miranda, DR and Arrazati, D and Cao, R and Chen, J and Liu, Y and Brown, D and Marshall, G},
title = {SRN-901, a Novel Longevity Drug, Extends Lifespan and Healthspan by Targeting Multiple Aging Pathways.},
journal = {Drug design, development and therapy},
volume = {20},
number = {},
pages = {594895},
pmid = {42011226},
issn = {1177-8881},
mesh = {Animals ; *Longevity/drug effects ; Mice ; *Aging/drug effects/metabolism ; Male ; Mice, Inbred C57BL ; Niacinamide/analogs & derivatives/pharmacology ; },
abstract = {INTRODUCTION: Developing interventions to delay aging and improve lifespan and healthspan is a critical goal in aging research. Individual geroprotective compounds fail to address the complexity, interconnectedness, and dynamic nature of biological systems, limiting success in significantly extending lifespan and improving health. This study investigates the effects of SRN-901-a novel oral combinatorial drug that consists of urolithin A, quercetin, nicotinamide riboside, alpha-lipoic acid, and Seragon's SRN-820-on lifespan extension, frailty reduction, disease-related gene expression pathways, metabolic aging, and the proteome in 18-month-old mice fed a Western diet.

RESULTS: SRN-901-treated mice showed a significant increase of 33% in median remaining lifespan compared to placebo-treated mice. Cox proportional hazards analysis revealed a hazard ratio of 0.54, indicating that SRN-901 treatment was associated with a 46% reduction in the hazard of death. While rapamycin increased lifespan in adult mice, nicotinamide mononucleotide (NMN), and nicotinamide riboside (NR) did not show significant differences in median lifespan compared to placebo. SRN-901 protected mice against increased frailty during aging, with baseline-normalized scores rising to 1.17 in treated mice and 1.57 in controls, corresponding to a 70% attenuation of frailty progression between pre-treatment (D-14) and post-treatment (D128; p < 0.001). Transcriptomic analyses revealed that SRN-901 modulates gene expression across pathways implicated in aging biology, including inflammation, apoptosis, and DNA repair, as well as gene sets associated with neurodegenerative disorders, including Alzheimer's disease. Metabolic profiling revealed that SRN-901 was associated with attenuation of several age-related metabolic shifts, resulting in a blood metabolite profile that more closely resembled that of younger mice. The upregulation of glutathione metabolism and other longevity-related pathways underscores SRN-901's role in enhancing cellular defenses against oxidative stress and maintaining metabolic health.

DISCUSSION: These results highlight SRN-901 as a promising multi-compound candidate for extending lifespan and healthspan by targeting multiple aging pathways.},
}

Animals
*Longevity/drug effects
Mice
*Aging/drug effects/metabolism
Male
Mice, Inbred C57BL
Niacinamide/analogs & derivatives/pharmacology

@article {pmid42011967,
year = {2026},
author = {Nowell, J and Crook, H and de Leon, MJ and Edison, P},
title = {Advances in the drug treatment of Alzheimer's disease: pathophysiology and mechanisms of action.},
journal = {BMJ (Clinical research ed.)},
volume = {393},
number = {},
pages = {78881},
doi = {10.1136/bmj-2023-078881},
pmid = {42011967},
issn = {1756-1833},
mesh = {Humans ; *Alzheimer Disease/drug therapy/physiopathology/metabolism ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; Brain/pathology/metabolism ; },
abstract = {Alzheimer's disease, the leading cause of dementia, is a multifactorial disorder involving amyloid beta (Aβ) and tau deposition, impaired glucose metabolism, neuroinflammation, mitochondrial dysfunction, insulin resistance, and progressive brain atrophy. Anti-Aβ therapies have shown clinical efficacy and are licensed in several countries. Amyloid related imaging abnormalities remain a key safety concern, and reimbursement varies across healthcare systems. The mechanisms underlying continued cognitive decline after Aβ clearance remain unclear and might be independent of amyloid pathology. Because Alzheimer's disease involves multiple pathological processes, effective management will likely require combination treatments addressing tau aggregation, neuroinflammation, synaptic loss, and metabolic dysfunction. Numerous compounds targeting these mechanisms are currently in late stage development for both early and advanced disease. These emerging approaches represent a shift toward multimodal, disease modifying strategies designed to improve patient outcomes and quality of life. Here, we review recent therapeutic advances in Alzheimer's disease and provide perspectives on novel treatment strategies.},
}

Humans
*Alzheimer Disease/drug therapy/physiopathology/metabolism
Amyloid beta-Peptides/metabolism
tau Proteins/metabolism
Brain/pathology/metabolism

@article {pmid42012375,
year = {2026},
author = {Nakashima, S and Sato, K and Niimi, Y and Aso, S and Yasunaga, H and Satake, W and Iwatsubo, T},
title = {Early adoption of lecanemab in Japan (December 2023-December 2024): Pretreatment diagnostic timelines from the DeSC claims database.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261443634},
doi = {10.1177/13872877261443634},
pmid = {42012375},
issn = {1875-8908},
abstract = {Using the Japanese DeSC claims database, we described pretreatment timelines for lecanemab initiation during early rollout (December 2023-December 2024). We identified 76 patients (mean age 74.6 years; 34.2% men) from 45 institutions. Mean time to first infusion was 103.9 days from cognitive assessment and 63.1 days from MRI. PET-to-infusion was 30.9 days, whereas cerebrospinal fluid (CSF) sampling-to-infusion was 85.8 days; the post-test interval remained longer after CSF (Bonferroni-adjusted p = 0.015). Although this claims-based snapshot may not represent all practice in Japan, it suggests that the CSF-based pathway can be associated with a longer post-test interval before treatment initiation.},
}

@article {pmid42012388,
year = {2026},
author = {Hildebrandt, H and Duning, T and Holland-Letz, M},
title = {Is there a cognitive measure of neurodegeneration for amyloid-Aβ-ratio probable Alzheimer's disease patients?.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261444308},
doi = {10.1177/13872877261444308},
pmid = {42012388},
issn = {1875-8908},
abstract = {BackgroundRecent developments in the assessment of Alzheimer's disease (AD) have centered on differential diagnostic questions. Only a few studies have aimed to identify neuropsychological measures that allow the prediction of disease progression. However, this question is central to informing patients about their diagnosis and to decisions regarding the urgency and timing of treatment escalation.ObjectiveWe analyzed which, if any, neuropsychological test results reflect the extent of neurodegenerative progression.MethodsThis retrospective analysis included 290 patients divided into an Aβ-ratio + group (n = 146; AD biomarker profile) and an Aβ-ratio- group (n = 144; non-AD biomarker profile). The Aβ-ratio + group was further divided into four t-tau quartiles. The Aβ-ratio- group was subdivided into patients with normal (n = 94) or elevated t-tau (n = 50).ResultsRegression and variance analyses demonstrated a correlation between Trail Making Test B (TMT-B) performance and t-tau levels in patients with an Aβ-ratio+, driven by differences between low and high tau values, but not in Aβ-ratio- patients. Several additional statistical control analyses endorsed this finding.ConclusionsWe conclude that, for Aβ-ratio + patients, TMT-B performance may serve as a clinically accessible indicator of tau-related disease activity and the extent of neurodegeneration and may help identify patients at risk of faster progression if replicated in longitudinal studies.},
}

@article {pmid42012422,
year = {2026},
author = {Xu, R and Ma, X and Wu, L and Yin, D and Zhao, L and Zhou, M and Yao, Y and Lin, R and Li, W and Yu, K},
title = {Transcranial Direct Current Stimulation Improves Cognitive Dysfunction in Amyloid Precursor Protein/Presenilin 1 Mice by Promoting Alternative Polarization of Microglia and Amyloid-Β Degradation.},
journal = {Neuromodulation : journal of the International Neuromodulation Society},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neurom.2026.03.007},
pmid = {42012422},
issn = {1525-1403},
abstract = {OBJECTIVE: This study investigated the mechanisms by which transcranial direct current stimulation (tDCS) alleviated Alzheimer's disease (AD) progression.

MATERIALS AND METHODS: Amyloid precursor protein (APP)/human presenilin 1 (PS1) transgenic mice (AD model) received tDCS (0.2 mA, anode electrode placed on the left frontal skull, 20 min/d for two weeks) and the NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) activator nigericin. Behavior tests evaluated spatial learning, recognition memory, and spontaneous exploration abilities in mice. Histopathologic changes in the hippocampal cornu ammonis area 1 (CA1) region and Aβ1-42 deposition were observed using histologic staining and immunohistochemistry. Enzyme-linked immunosorbent assay was used to measure Aβ1-40 and Aβ1-42 expression. Classical microglia (M1)/alternative microglia (M2) polarization, inflammatory factors, and oxidative stress levels were assessed through immunofluorescence and kits. NLRP3 inflammasome indicators were detected by reverse transcription quantitative polymerase chain reaction and western blot.

RESULTS: After tDCS treatment, APP/PS1 mice exhibited shortened escape latency, increased platform crossings, and an elevated discrimination index. In the open field test, total movement distance and time spent in the center zone increased. The Aβ1-42/40 ratio in the mouse hippocampal CA1 region decreased by 20.8%, whereas neurons and Nissl bodies increased, indicating that tDCS improved cognitive function. tDCS reduced M1 polarization, increased M2 polarization, and reduced neuroinflammation and oxidative stress in the hippocampal CA1 region of APP/PS1 mice. Moreover, tDCS suppressed microglial NLRP3/caspase-1 pathway activation and Aβ deposition in APP/PS1 mice. NLRP3/caspase-1 pathway activation partially reversed effects of tDCS on APP/PS1 mice.

CONCLUSION: This study highlights the potential therapeutic value of tDCS in AD mice. It reveals that tDCS promotes hippocampal microglial M2 polarization and Aβ degradation to curtail NLRP3/caspase-1 inflammasome pathway activation, thereby improving cognitive function in APP/PS1 mice.},
}

@article {pmid42012542,
year = {2026},
author = {Tu, X and Fang, M and Yan, Y and Liu, Y and Yu, J and Chen, L and Zhang, L and Huang, C and Fan, S},
title = {The neuroprotective effect of Cucurbitacin B against Aβ and tau toxicities requires functional HDAC6 and stress granule pathways.},
journal = {Biogerontology},
volume = {27},
number = {3},
pages = {},
pmid = {42012542},
issn = {1573-6768},
support = {24ZR1466100//Natural Science Foundation of Shanghai Municipality/ ; 25PJD123//Shanghai Magnolia Talent Plan of Shanghai - Pujiang Talents Program/ ; QNKJ2025007//Eastern Talent Program - Science and Technology Platform of Shanghai/ ; },
mesh = {*Histone Deacetylase 6/metabolism ; Animals ; *Triterpenes/pharmacology ; *Amyloid beta-Peptides/toxicity/metabolism ; *Neuroprotective Agents/pharmacology ; Caenorhabditis elegans ; Humans ; *tau Proteins/metabolism/toxicity ; *Stress Granules/metabolism/drug effects ; *Alzheimer Disease/metabolism/drug therapy ; Caenorhabditis elegans Proteins/metabolism ; },
abstract = {Alzheimer's disease (AD) is characterized by proteostasis collapse driven by amyloid-β (Aβ) plaques and tau tangles. Dysregulation of stress granule (SG) dynamics and aberrant histone deacetylase 6 (HDAC6) activity are emerging as pivotal pathogenic mechanisms promoting neurodegeneration. Here, we identify that Cucurbitacin B (CB), a natural triterpenoid, acts as a potent SG inducer that confers broad-spectrum neuroprotection. Mechanistically, we demonstrate a novel "recruit-and-sequester" model: CB promotes the assembly of HDAC6-recuited SGs, thereby physically sequestering HDAC6 and functionally inhibiting its deacetylase activity. In Caenorhabditis elegans (C. elegans) and mammalian cell models, CB treatment significantly alleviated Aβ oligomer-induced cytotoxicity and tau hyperphosphorylation. Notably, the neuroprotective efficacy of CB was abolished by the genetic knockdown of core SG components (gtbp-1/G3BP1, tiar-1/TIA1) or hda-6/HDAC6, confirming that its therapeutic action relies on the integrity of the HDAC6-SG. Our findings highlight the potential of modulating SG dynamics to spatially regulate HDAC6, offering a novel therapeutic strategy for AD.},
}

*Histone Deacetylase 6/metabolism
Animals
*Triterpenes/pharmacology
*Amyloid beta-Peptides/toxicity/metabolism
*Neuroprotective Agents/pharmacology
Caenorhabditis elegans
Humans
*tau Proteins/metabolism/toxicity
*Stress Granules/metabolism/drug effects
*Alzheimer Disease/metabolism/drug therapy
Caenorhabditis elegans Proteins/metabolism

@article {pmid42013009,
year = {2026},
author = {Botta, D and Bernetti, C and Hutuca, I and Ojeda Esparza, JF and Sveikata, L and Lovblad, KO and Kurz, FT},
title = {Beyond the Leak: Advanced MRI Assessment of the Blood-Brain Barrier in Neurodegeneration.},
journal = {Neuro-degenerative diseases},
volume = {},
number = {},
pages = {1-25},
doi = {10.1159/000552173},
pmid = {42013009},
issn = {1660-2862},
abstract = {The blood-brain barrier (BBB) is a specialized multicellular interface that maintains the CNS's tightly regulated microenvironment. BBB disruption is increasingly recognized as a key feature of neurodegeneration, documented across disorders including Alzheimer's disease (AD), Parkinson's disease (PD), and cerebral small vessel disease (cSVD). While the extent to which BBB breakdown is a cause or consequence of neuronal pathology remains unclear, its pronounced presence in disease states suggests a significant contributory role in progression. Advances in MRI have revolutionized our ability to visualize and quantify these alterations in vivo. This review provides a neuroradiological overview of advanced MRI approaches and their specific biomarkers, specifically Dynamic Contrast-Enhanced MRI (DCE) with Ktrans and Arterial Spin Labeling (ASL) with kw, detailing disease-specific BBB signatures in major neurodegenerative disorders. Current technological strides, including ultra-high-field MRI and AI-assisted post-processing, are pushing the sensitivity needed to detect subtle BBB changes. Ultimately, with technical refinement and standardization, MRI methods are transitioning from research tools into candidate neurovascular biomarkers with growing potential for early diagnosis, treatment monitoring, and longitudinal follow-up, pending multicenter standardization and normative validation.},
}

@article {pmid42013076,
year = {2026},
author = {Jain, S and Tunc, EB and Grossberg, GT},
title = {Pharmacotherapeutic landscape for the management of agitation associated with Alzheimer's disease.},
journal = {Expert opinion on pharmacotherapy},
volume = {},
number = {},
pages = {1-14},
doi = {10.1080/14656566.2026.2662949},
pmid = {42013076},
issn = {1744-7666},
abstract = {INTRODUCTION: Agitation associated with Alzheimer's disease (AAD) is common, persistent, and strongly linked to caregiver burden, emergency care, and institutionalization. Pharmacologic options have historically been limited by modest efficacy and safety liabilities in the geriatric population, creating a major treatment gap.

AREAS COVERED: This narrative review summarizes established and emerging pharmacotherapies for AAD, emphasizing comparative efficacy, geriatric-relevant safety, and real-world feasibility. A literature search was conducted in PubMed/MEDLINE and ClinicalTrials.gov from database inception through 31 January 2026, prioritizing the most recent decade when applicable, and complemented these searches with hand searches of key trials, meta-analyses, guidelines, and publicly available regulatory or sponsor communications for late-stage programs. Evidence is synthesized qualitatively due to heterogeneity in definitions and outcomes. We discuss antipsychotics, serotonergic agents, drugs with negative trials, and pipeline approaches such as dextromethorphan-based combinations and adrenergic strategies.

EXPERT OPINION: The field is shifting from broad off-label prescribing toward phenotype-informed, trial-validated treatments. Brexpiprazole establishes regulatory feasibility, while dextromethorphan-based combinations, particularly AXS-05, appear promising, including signals for durability. Progress will depend on harmonized outcomes, longer-term safety data, and pragmatic trials that prioritize function, caregiver impact, and crisis prevention.},
}

@article {pmid42000569,
year = {2026},
author = {Schelter, BO and Shiells, H and Lo, S and Nazlee, N and Evans, E and Bentham, P and Gauthier, S and Zetterberg, H and Wilcock, GK and Froelich, L and Burns, A and MacSweeney, E and Ballard, C and Yu, JT and Choon, TS and Asvatourian, V and Muehlemann, N and Priel, J and Kook, K and Sullivan, T and Downie, D and Miller, S and Pringle, C and Storey, JMD and Baddeley, T and Harrington, CR and Staff, R and Sandu, AL and Hull, C and Stefanacci, R and Wischik, CM and , },
title = {Assessment of clinical and neuroimaging efficacy of treatment targeting tau pathology in mild cognitive impairment and mild to moderate Alzheimer's disease with hydromethylthionine mesylate using external control data.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {6},
pages = {100560},
doi = {10.1016/j.tjpad.2026.100560},
pmid = {42000569},
issn = {2426-0266},
abstract = {BACKGROUND: Hydromethylthionine mesylate (HMTM) targets tau pathology and also has tau-independent symptomatic activity. A traditional randomised placebo-controlled trial (RCT) was precluded by loss of blinding due to urinary colouration and therapeutic activity at the minimum dose required to maintain blinding.

OBJECTIVE: To evaluate the efficacy of HMTM in participants with mild cognitive impairment (MCI) and mild to moderate dementia due to Alzheimer's disease (AD).

METHODS: Because a traditional RCT was not feasible without loss of blinding, we compared HMTM 16 mg/day in TRx-237-039 with propensity score matched true placebo controls from the FDA-sponsored Critical Path for AD (CPAD) database with the same inclusion/exclusion criteria (protocol TRx-237-080). We also compared HMTM 16 mg/day with matched natural history controls from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and with a meta-analysis of placebo arms from trials in comparable populations in analyses specified prior to the 104-week database lock of TRx-237-039.

PARTICIPANTS: Propensity score matching yielded 127 pairs (HMTM n = 127; CPAD placebo n = 127) in the CPAD comparison, and 189 pairs in the ADNI comparison. A total of 218 receiving HMTM 16 mg/day were compared with meta-analytic controls (n = 1805-8567).

INTERVENTION: HMTM 16mg/day MEASUREMENTS: Primary outcomes in TRx-237-080 were change from baseline to 78 weeks in ADAS-Cog13 and whole brain volume (WBV). CDR-Sum of Boxes (CDR-SB) and CDR-Global were analysed at 104 weeks. ADAS-cog11 and WBV were analysed in ADNI comparisons, and ADAS-cog11, ADCS-ADL23, CDR-SB and WBV were analysed in meta-analytic comparisons.

RESULTS: Compared with matched CPAD placebo, HMTM 16 mg/day produced statistically significant differences in change on ADAS-Cog13 (p < 0.0001) and WBV at 78 (primary; p < 0.0001) and 104 weeks (p < 0.0001), and CDR-SB differed significantly overall (104-weeks; p < 0.001) and in MCI (p = 0.007). The odds of progressing to a more advanced CDR-Global stage were lower with HMTM (overall OR 0.31) and particularly in MCI (OR 0.15) versus CPAD placebo. Clinical and brain atrophy outcomes were similarly statistically significant in comparisons with ADNI case-matched natural history data and in meta-analytic comparisons.

CONCLUSION: Comparisons of HMTM treatment with CPAD, ADNI, and meta-analytic controls provide evidence consistent with clinical benefit HMTM. It has the potential to offer an accessible oral treatment option which could be delivered with minimal patient/physician burden.},
}

@article {pmid42001186,
year = {2026},
author = {Zheng, W and Geng, D and Wang, A and Li, Z and Liu, A and Chen, S and Wang, Q and Su, C and Yan, Z and Yin, Y and Xu, G},
title = {Gamma low field magnetic stimulation ameliorates pathophysiological damage and cognitive impairments in AD mice.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02052-1},
pmid = {42001186},
issn = {1758-9193},
support = {52277230//National Natural Science Foundation of China/ ; SJZZXB24006//Science and Technology Cooperation Special Project of Shijiazhuang/ ; 25292001D//Hebei Province Provincial Science and Technology Programme Project International Science and Technology Co-operation Special Project/ ; 2022YFC2402203//National Key R&D Program of China/ ; },
abstract = {BACKGROUND: The normal functioning of gamma rhythms is crucial for maintaining brain health, while their abnormalities are closely associated with various neurological disorders, particularly Alzheimer's disease. Gamma stimulation modalities including auditory, visual, electrical, and strong magnetic approaches have all demonstrated potential therapeutic effects for AD, with substantial research findings continuously emerging. However, 40 Hz gamma low field magnetic stimulation(gamma-LFMS) remains unexplored.

METHODS: To investigate this question, we applied pulsed magnetic fields with a magnetic field strength of 10 mT and frequency of 40 Hz (2 × 30 min/day) to 9-month-old APP/PS1 double transgenic AD model mice for 18 consecutive days, and evaluated changes in spatial memory capacity, hippocampal neural network characteristics, and amyloid protein 42 content in AD mice.

RESULTS: Gamma-LFMS significantly enhanced spatial memory performance in AD mice, increased theta-gamma phase-amplitude coupling and gamma band power in the hippocampal CA1 region, showed a trend toward desynchronization in low gamma, and effectively reduced hippocampal β-amyloid42 burden.

CONCLUSIONS: This study demonstrates for the first time that gamma-LFMS effectively ameliorates pathophysiological alterations and spatial memory deficits in AD mice. These findings address a critical knowledge gap regarding the effects of gamma-LFMS on AD pathology and provide a theoretical foundation for developing cost-effective home-based prevention and treatment devices applicable throughout the lifespan.},
}

@article {pmid42001306,
year = {2026},
author = {Thakur, A and Rana, M and Vanjani, S and Liou, KC and Taliyan, R and Nepali, K and Yang, CH},
title = {Multi-Targeting Ligands as Prospective Therapeutics for Alzheimer's Disease, a Prevalent Neurodegenerative Disorder: Mechanistic Insights, Emerging Targets and Drug Discovery Campaigns.},
journal = {Medicinal research reviews},
volume = {},
number = {},
pages = {},
doi = {10.1002/med.70047},
pmid = {42001306},
issn = {1098-1128},
support = {NSTC 112-2320-B-038-018-MY3//National Science and Technology Council, Taiwan/ ; },
abstract = {Alzheimer's disease (AD) is a debilitating neurodegenerative condition characterized by progressive cognitive impairment, memory deterioration, and neuronal dysfunction. Its complex pathophysiology involves multiple interlinked processes, including amyloid-β (Aβ) aggregation, tau hyperphosphorylation, oxidative stress, neuroinflammation, synaptic dysfunction, and cholinergic deficits. Current FDA-approved therapies provide only symptomatic relief and fail to halt disease progression, highlighting the urgent need for more effective treatment strategies. This review provides a comprehensive overview of the pathological mechanisms underlying AD and the emerging therapeutic targets for the design of tractable anti-AD scaffolds, namely, acetylcholinesterase, beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), glycogen synthase kinase-3β (GSK3β), dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A), histone deacetylases (HDACs), and soluble epoxide hydrolase (sEH). Emphasis is placed on the paradigm shift from single-target therapies to multitarget-directed ligands (MTDLs), which are increasingly recognized as promising tools to tackle AD's multifactorial pathology. We also discuss recent advances in medicinal chemistry and structure-guided drug discovery campaigns aimed at developing pharmacologically optimized, BBB-penetrant MTDLs. By consolidating mechanistic insights with therapeutic innovation, this review aims to facilitate the development of next-generation therapeutics with enhanced efficacy and disease-modifying potential in AD.},
}

@article {pmid42002723,
year = {2026},
author = {Sukreet, S and Kim, EK and Petersen, M and Zhang, F and O'Bryant, SE and Rafii, MS and Rissman, RA},
title = {Precision medicine for Alzheimer's disease in Down syndrome.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71398},
doi = {10.1002/alz.71398},
pmid = {42002723},
issn = {1552-5279},
support = {AG073979//NIH/NIA/ ; R61/R33AG066543//NIH/NIA/ ; },
mesh = {Humans ; *Down Syndrome/complications ; *Alzheimer Disease/drug therapy/diagnosis/blood/complications ; *Precision Medicine/methods ; Male ; Female ; Biomarkers/blood ; Middle Aged ; *Vitamin E/therapeutic use ; Proteomics ; Aged ; Neuropsychological Tests ; Support Vector Machine ; Extracellular Vesicles/metabolism ; },
abstract = {INTRODUCTION: Down syndrome (DS) exhibits a genetic form of Alzheimer's disease (AD). We used a blood-based proteomic algorithm to predict cognitive status, treatment responders, and change to vitamin E in DS adults from a completed clinical trial, "Vitamin E in Aged Persons with Down Syndrome," which originally showed no significant cognitive benefit using the primary endpoint cognition (Brief Praxis Test [BPT]).

METHODS: Plasma and extracellular vesicle (EV; astrocytic and neuronal) biomarkers were assayed at baseline and 36 months (n = 138 each). Cognitive response was measured using combined scores from the BPT, vocabulary, and behavior and function DS tests. Support vector machine (SVM) analyses predicted diagnostic and treatment responders and change accuracy.

RESULTS: SVM classified demented versus non-demented with up to 99% accuracy and predicted treatment response and changes with up to 100% accuracy in plasma and EV.

DISCUSSION: Our study supports blood-based screening and precision diagnostics for AD therapy in DS.},
}

Humans
*Down Syndrome/complications
*Alzheimer Disease/drug therapy/diagnosis/blood/complications
*Precision Medicine/methods
Male
Female
Biomarkers/blood
Middle Aged
*Vitamin E/therapeutic use
Proteomics
Aged
Neuropsychological Tests
Support Vector Machine
Extracellular Vesicles/metabolism

@article {pmid42004236,
year = {2026},
author = {Zhang, B and Zhang, M},
title = {Metabolic Regulatory Networks in Ferroptosis During Alzheimer's Disease, Mechanisms of Glial Cell Action, and Pathological Correlations with Neuritic Plaques.},
journal = {International journal of general medicine},
volume = {19},
number = {},
pages = {596584},
pmid = {42004236},
issn = {1178-7074},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disease with a complex pathological mechanism, which is still poorly understood. Ferroptosis is a type of non-apoptotic programmed cell death. Many recent studies have found that ferroptosis is closely related to the occurrence and development of AD. This article explains the main theoretical basis of ferroptosis in the pathological development of AD, and systematically analyzes the synergistic pathological network of multiple pathways caused by iron metabolism disorder, abnormal lipid peroxidation, and abnormal amino acid metabolism. This article mainly focuses on the dual regulation mechanism and molecular mechanism of microglia, astrocytes, and oligodendrocytes in the process of ferroptosis. This article studies the two-way relationship between neuritic plaques (NP) and ferroptosis, and the relationship between NP and dystrophic neurites, inflammatory response, and abnormal tau phosphorylation. Based on the existing research, we propose several unanswered questions and possible targeted research directions to provide a theoretical reference for the study of AD pathogenesis and the exploration of intervention strategies.},
}

@article {pmid42004570,
year = {2026},
author = {Shajahan, SR and Hein, ZM and Muhammad, H and Mustafa, MZ and Kumari, Y and Jazuli, I and Zulkapli, A and Shari, N and Nassir, CMNCM and Ramli, MDC},
title = {Stingless bee honey alleviates cognitive deficits and hippocampal neurodegeneration in an Alzheimer's model: Behavioural, neurochemical, and histological analyses.},
journal = {AIMS neuroscience},
volume = {13},
number = {1},
pages = {1-28},
pmid = {42004570},
issn = {2373-7972},
abstract = {Stingless bee honey (SBH), widely consumed in Southeast Asia, is traditionally valued for its medicinal and nutritional properties, particularly in promoting brain health. However, its neuroprotective potential against Alzheimer's disease (AD) remains underexplored. In this study, we investigated the therapeutic effects and safety of SBH in a rat model of AD. A total of sixty-three adult male Sprague-Dawley rats (180-200 g) were used: Fifteen were assigned to three toxicity groups (500, 750, 1000 mg/kg; n = 5) and forty-eight to six therapeutic groups (n = 8): Normal control, AD (AlCl3 + D-gal), AD + Donepezil (1.5 mg/kg), and three SBH-treated groups (500, 750, 1000 mg/kg). Alzheimer-like pathology was induced by aluminium chloride (150 mg/kg) and D-galactose (300 mg/kg), followed by 14 days of treatment. Toxicity was evaluated through liver and kidney histopathology, while behavioural performance was assessed using the Open Field Test and Morris Water Maze. Serum dopamine, serotonin, corticosterone, and acetylcholinesterase activity were quantified via ELISA, and hippocampal morphology was examined histologically. SBH administration produced no signs of systemic toxicity and significantly improved exploratory activity and spatial learning, with the most pronounced effects at 750 mg/kg. Biochemical assays showed reduced acetylcholinesterase and corticosterone levels alongside increased dopamine and serotonin concentrations. Histological analysis confirmed neuronal preservation and reduced hippocampal damage. Inclusion of Donepezil as a positive control enabled comparison with a standard pharmacological treatment. These findings demonstrated that SBH is a safe and promising natural therapeutic capable of alleviating cognitive deficits associated with AD.},
}

@article {pmid42005438,
year = {2026},
author = {Fleig, K and Haslinger, L and Dawczynski, C and Kolassa, IT},
title = {Omega-3 fatty acids in mental disorders: from neurobiological and metabolic mechanisms to therapeutic potential.},
journal = {Frontiers in nutrition},
volume = {13},
number = {},
pages = {1748196},
pmid = {42005438},
issn = {2296-861X},
abstract = {Nutritional psychiatry is an emerging field. Micro- and macro-nutrients play a role in energy metabolism and the regulation of inflammation; particularly, an insufficient dietary intake of omega-3 fatty acids and an imbalanced intake of omega-6/omega-3 fatty acids, with a shift toward increased inflammation, are of relevance for the pathophysiology of mental disorders. This review summarizes evidence on the role of omega-3 fatty acids in the pathophysiology of mental disorders (schizophrenia, affective and anxiety disorders, post-traumatic stress disorder, and eating disorders), neurodevelopmental disorders (attention-deficit/hyperactivity disorder and autism spectrum disorder) and neurodegenerative disorders (Alzheimer's disease) and explores potential treatment implications. In addition, the underlying neurobiological mechanisms through which omega-3 fatty acids might exert a protective effect are also discussed. Despite methodological variability and heterogeneous results, an increasing body of evidence suggests that omega-3 deficiency and altered fatty acid profiles are modifiable risk factors and potential biomarkers for mental disorders. The integration of omega-3 supplementation as an adjuvant to state-of-the-art therapy offers the potential for a low-risk intervention with meaningful clinical outcomes. However, clinical monitoring is recommended to avoid adverse effects and to adjust the dosage according to individual and disease-specific factors.},
}

@article {pmid42005580,
year = {2026},
author = {Imran, S and Patel, M and Noroozifar, M and Kerman, K},
title = {Recent advances towards BACE1 drug discovery and therapeutics design.},
journal = {RSC medicinal chemistry},
volume = {},
number = {},
pages = {},
pmid = {42005580},
issn = {2632-8682},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and memory loss. A key feature of AD is the accumulation of amyloid beta (Aβ) peptides in the form of extracellular plaques. The amyloid cascade hypothesis suggests that the pathogenesis of AD is initiated by the cleavage of amyloid precursor protein (APP) by β-site amyloid precursor protein cleaving enzyme 1 (BACE1). Numerous therapeutic approaches have been pursued to target BACE1 due to its crucial role in AD. However, the complexity of AD and the localization of BACE1 in the brain have posed challenges, leading to the failure of clinical trials and, in some cases, even exacerbating disease progression. Specifically, the blood-brain barrier (BBB) prevents the entry of many molecules, making BACE1 a difficult target to approach. Recent advancements in BACE1 therapy have shifted the focus from traditional enzyme inhibitor-based therapeutics to modulators, antibody therapy, and gene therapy. These approaches offer several advantages, including the ability to efficiently cross the BBB and provide targeted treatment. In this review, we explore the latest developments in modulators, antibody therapy, and gene therapy targeting BACE1 to combat AD. These approaches offer a promising avenue to mitigate the progression of AD and provide a novel therapeutic strategy.},
}